TY  - JOUR
AU  - Jovanović, Aleksa
AU  - Tošić, Nataša
AU  - Marjanović, Irena
AU  - Komazec, Jovana
AU  - Zukić, Branka
AU  - Nikitović, Marina
AU  - Ilić, Rosanda
AU  - Grujičić, Danica
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2023
UR  - https://www.mdpi.com/1422-0067/24/24/17387
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2279
AB  - Central nervous system (CNS) tumors comprise around 20% of childhood malignancies. Germline variants in cancer predisposition genes (CPGs) are found in approximately 10% of pediatric patients with CNS tumors. This study aimed to characterize variants in CPGs in pediatric patients with CNS tumors and correlate these findings with clinically relevant data. Genomic DNA was isolated from the peripheral blood of 51 pediatric patients and further analyzed by the next-generation sequencing approach. Bioinformatic analysis was done using an “in-house” gene list panel, which included 144 genes related to pediatric brain tumors, and the gene list panel Neoplasm (HP:0002664). Our study found that 27% of pediatric patients with CNS tumors have a germline variant in some of the known CPGs, like ALK, APC, CHEK2, ELP1, MLH1, MSH2, NF1, NF2 and TP53. This study represents the first comprehensive evaluation of germline variants in pediatric patients with CNS tumors in the Western Balkans region. Our results indicate the necessity of genomic research to reveal the genetic basis of pediatric CNS tumors, as well as to define targets for the application and development of innovative therapeutics that form the basis of the upcoming era of personalized medicine.
T2  - International Journal of Molecular Sciences
T1  - Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors
IS  - 24
SP  - 17387
VL  - 24
DO  - 10.3390/ijms242417387
ER  - 

@article{
author = "Jovanović, Aleksa and Tošić, Nataša and Marjanović, Irena and Komazec, Jovana and Zukić, Branka and Nikitović, Marina and Ilić, Rosanda and Grujičić, Danica and Janić, Dragana and Pavlović, Sonja",
year = "2023",
abstract = "Central nervous system (CNS) tumors comprise around 20% of childhood malignancies. Germline variants in cancer predisposition genes (CPGs) are found in approximately 10% of pediatric patients with CNS tumors. This study aimed to characterize variants in CPGs in pediatric patients with CNS tumors and correlate these findings with clinically relevant data. Genomic DNA was isolated from the peripheral blood of 51 pediatric patients and further analyzed by the next-generation sequencing approach. Bioinformatic analysis was done using an “in-house” gene list panel, which included 144 genes related to pediatric brain tumors, and the gene list panel Neoplasm (HP:0002664). Our study found that 27% of pediatric patients with CNS tumors have a germline variant in some of the known CPGs, like ALK, APC, CHEK2, ELP1, MLH1, MSH2, NF1, NF2 and TP53. This study represents the first comprehensive evaluation of germline variants in pediatric patients with CNS tumors in the Western Balkans region. Our results indicate the necessity of genomic research to reveal the genetic basis of pediatric CNS tumors, as well as to define targets for the application and development of innovative therapeutics that form the basis of the upcoming era of personalized medicine.",
journal = "International Journal of Molecular Sciences",
title = "Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors",
number = "24",
pages = "17387",
volume = "24",
doi = "10.3390/ijms242417387"
}

Jovanović, A., Tošić, N., Marjanović, I., Komazec, J., Zukić, B., Nikitović, M., Ilić, R., Grujičić, D., Janić, D.,& Pavlović, S.. (2023). Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors. in International Journal of Molecular Sciences, 24(24), 17387.
https://doi.org/10.3390/ijms242417387

Jovanović A, Tošić N, Marjanović I, Komazec J, Zukić B, Nikitović M, Ilić R, Grujičić D, Janić D, Pavlović S. Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors. in International Journal of Molecular Sciences. 2023;24(24):17387.
doi:10.3390/ijms242417387 .

Jovanović, Aleksa, Tošić, Nataša, Marjanović, Irena, Komazec, Jovana, Zukić, Branka, Nikitović, Marina, Ilić, Rosanda, Grujičić, Danica, Janić, Dragana, Pavlović, Sonja, "Germline Variants in Cancer Predisposition Genes in Pediatric Patients with Central Nervous System Tumors" in International Journal of Molecular Sciences, 24, no. 24 (2023):17387,
https://doi.org/10.3390/ijms242417387 . .

TY  - CONF
AU  - Karan-Đurašević, Teodora
AU  - Kaćanski, Nataša
AU  - Kostić, Tatjana
AU  - Marjanović, Irena
AU  - Tošić, Nataša
AU  - Perić, Jelena
AU  - Kolarović, Jovanka
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2113
AB  - Introduction: Childhood B-cell precursor acute lymphoblastic leukemic (BCP-ALL) can be traced back to
birth using leukemic clone-specific immunoglobulin heavy chain (IGH) rearrangements, implying prenatal origin of this disease. The aim of this study was to analyze neonatal blood spots (Guthrie cards) of
childhood BCP-ALL patients for the presence of clonotypic IGH rearrangements.
Methods: The study enrolled 24 patients aged 1 to 9.6 years. Based on the sequences of IGH rearrangements identified in diagnostic lymphoblasts, 2 patient-specific primers were designed for each patient
and used in semi-nested PCR for the detection of preleukemic clones at birth.
Results: Clonotypic IGH rearrangements were detected in neonatal blood spots of 54.2% of patients. In
two cases that had double IGH rearrangements at diagnosis, only one rearrangement was present at
birth, while in the third case both leukemic rearrangements were detected in neonatal blood. Guthrie
card-positive findings were significantly more frequent in children ≤5 years of age than in older children
(p=0.011). Regarding patients’characteristics at birth and at diagnosis, Guthrie card-positivity was not associated with sex, birth weight and mother’s age, as well as with white blood cell count, percentage of
bone marrow blasts, immunophenotype and the presence of ETV6/RUNX1 and TCF3/PBX1 fusion genes
at diagnosis.
Conclusion: Our study confirms that a large proportion of childhood BCP-ALL originates in utero, regardless of the molecularsubtype defined by chromosomal aberrations. The latency period to the overt
leukemia depends on the presence of preleukemic clone at birth, as well as on the postnatal transforming genetic events.
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - Detection of preleukemic clones in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia
EP  - 59
SP  - 59
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2113
ER  - 

@conference{
author = "Karan-Đurašević, Teodora and Kaćanski, Nataša and Kostić, Tatjana and Marjanović, Irena and Tošić, Nataša and Perić, Jelena and Kolarović, Jovanka and Janić, Dragana and Pavlović, Sonja",
year = "2023",
abstract = "Introduction: Childhood B-cell precursor acute lymphoblastic leukemic (BCP-ALL) can be traced back to
birth using leukemic clone-specific immunoglobulin heavy chain (IGH) rearrangements, implying prenatal origin of this disease. The aim of this study was to analyze neonatal blood spots (Guthrie cards) of
childhood BCP-ALL patients for the presence of clonotypic IGH rearrangements.
Methods: The study enrolled 24 patients aged 1 to 9.6 years. Based on the sequences of IGH rearrangements identified in diagnostic lymphoblasts, 2 patient-specific primers were designed for each patient
and used in semi-nested PCR for the detection of preleukemic clones at birth.
Results: Clonotypic IGH rearrangements were detected in neonatal blood spots of 54.2% of patients. In
two cases that had double IGH rearrangements at diagnosis, only one rearrangement was present at
birth, while in the third case both leukemic rearrangements were detected in neonatal blood. Guthrie
card-positive findings were significantly more frequent in children ≤5 years of age than in older children
(p=0.011). Regarding patients’characteristics at birth and at diagnosis, Guthrie card-positivity was not associated with sex, birth weight and mother’s age, as well as with white blood cell count, percentage of
bone marrow blasts, immunophenotype and the presence of ETV6/RUNX1 and TCF3/PBX1 fusion genes
at diagnosis.
Conclusion: Our study confirms that a large proportion of childhood BCP-ALL originates in utero, regardless of the molecularsubtype defined by chromosomal aberrations. The latency period to the overt
leukemia depends on the presence of preleukemic clone at birth, as well as on the postnatal transforming genetic events.",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "Detection of preleukemic clones in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia",
pages = "59-59",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2113"
}

Karan-Đurašević, T., Kaćanski, N., Kostić, T., Marjanović, I., Tošić, N., Perić, J., Kolarović, J., Janić, D.,& Pavlović, S.. (2023). Detection of preleukemic clones in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 59-59.
https://hdl.handle.net/21.15107/rcub_imagine_2113

Karan-Đurašević T, Kaćanski N, Kostić T, Marjanović I, Tošić N, Perić J, Kolarović J, Janić D, Pavlović S. Detection of preleukemic clones in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:59-59.
https://hdl.handle.net/21.15107/rcub_imagine_2113 .

Karan-Đurašević, Teodora, Kaćanski, Nataša, Kostić, Tatjana, Marjanović, Irena, Tošić, Nataša, Perić, Jelena, Kolarović, Jovanka, Janić, Dragana, Pavlović, Sonja, "Detection of preleukemic clones in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):59-59,
https://hdl.handle.net/21.15107/rcub_imagine_2113 .

TY  - JOUR
AU  - Kačanski, Nataša
AU  - Kolarović, Jovanka
AU  - Kostić, Tatjana
AU  - Marjanović, Irena
AU  - Janić, Dragana
AU  - Pavlović, Sonja
AU  - Karan-Đurašević, Teodora
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2213
AB  - Introduction
Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be traced back to birth using leukemic clone-specific immunoglobulin heavy chain (IGH) rearrangements, implying prenatal origin of this disease.

Methods
We retrospectively analyzed neonatal blood spots (Guthrie cards) of 24 patients with childhood BCP-ALL aged 1–9.6 years (median 3.1 years) for the presence of clonotypic IGH rearrangements identified in diagnostic bone marrow samples. Based on the sequences of IGH rearrangements, 2 patient-specific primers were designed for each patient and used in semi-nested polymerase chain reaction for the detection of preleukemic clones at birth.

Results
Clonotypic IGH rearrangements were detected in neonatal blood spots of 54.2% of patients (13/24). In two cases with double IGH rearrangements detected at diagnosis, only one rearrangement was present at birth, while in the third case both leukemic rearrangements were detected in neonatal blood. Guthrie card-positive findings were significantly more frequent in children ≤5 years of age than in older children (p = 0.011). Regarding patients' characteristics at birth and at diagnosis, Guthrie card-positivity was not associated with sex, birth weight and mother's age, as well as with white blood cell count, percentage of bone marrow blasts, immunophenotype and the presence of ETV6/RUNX1 and TCF3/PBX1 fusion genes at diagnosis.

Conclusion
Our study confirms that a large proportion of childhood BCP-ALL originates in utero, regardless of the molecular subtype defined by chromosomal aberrations. The observed trend toward younger age at diagnosis in Guthrie card-positive versus Guthrie card-negative patients implies that the age at diagnosis depends on the presence of preleukemic clone at birth, as well as on the timing of postnatal transforming genetic events.
PB  - John Wiley & Sons Ltd
T2  - International Journal of Laboratory Hematology
T1  - Presence of leukemic clone-specific immunoglobulin heavy chain rearrangements in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia
IS  - 6
VL  - 45
DO  - doi.org/10.1111/ijlh.14200
ER  - 

@article{
author = "Kačanski, Nataša and Kolarović, Jovanka and Kostić, Tatjana and Marjanović, Irena and Janić, Dragana and Pavlović, Sonja and Karan-Đurašević, Teodora",
year = "2023",
abstract = "Introduction
Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be traced back to birth using leukemic clone-specific immunoglobulin heavy chain (IGH) rearrangements, implying prenatal origin of this disease.

Methods
We retrospectively analyzed neonatal blood spots (Guthrie cards) of 24 patients with childhood BCP-ALL aged 1–9.6 years (median 3.1 years) for the presence of clonotypic IGH rearrangements identified in diagnostic bone marrow samples. Based on the sequences of IGH rearrangements, 2 patient-specific primers were designed for each patient and used in semi-nested polymerase chain reaction for the detection of preleukemic clones at birth.

Results
Clonotypic IGH rearrangements were detected in neonatal blood spots of 54.2% of patients (13/24). In two cases with double IGH rearrangements detected at diagnosis, only one rearrangement was present at birth, while in the third case both leukemic rearrangements were detected in neonatal blood. Guthrie card-positive findings were significantly more frequent in children ≤5 years of age than in older children (p = 0.011). Regarding patients' characteristics at birth and at diagnosis, Guthrie card-positivity was not associated with sex, birth weight and mother's age, as well as with white blood cell count, percentage of bone marrow blasts, immunophenotype and the presence of ETV6/RUNX1 and TCF3/PBX1 fusion genes at diagnosis.

Conclusion
Our study confirms that a large proportion of childhood BCP-ALL originates in utero, regardless of the molecular subtype defined by chromosomal aberrations. The observed trend toward younger age at diagnosis in Guthrie card-positive versus Guthrie card-negative patients implies that the age at diagnosis depends on the presence of preleukemic clone at birth, as well as on the timing of postnatal transforming genetic events.",
publisher = "John Wiley & Sons Ltd",
journal = "International Journal of Laboratory Hematology",
title = "Presence of leukemic clone-specific immunoglobulin heavy chain rearrangements in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia",
number = "6",
volume = "45",
doi = "doi.org/10.1111/ijlh.14200"
}

Kačanski, N., Kolarović, J., Kostić, T., Marjanović, I., Janić, D., Pavlović, S.,& Karan-Đurašević, T.. (2023). Presence of leukemic clone-specific immunoglobulin heavy chain rearrangements in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia. in International Journal of Laboratory Hematology
John Wiley & Sons Ltd., 45(6).
https://doi.org/doi.org/10.1111/ijlh.14200

Kačanski N, Kolarović J, Kostić T, Marjanović I, Janić D, Pavlović S, Karan-Đurašević T. Presence of leukemic clone-specific immunoglobulin heavy chain rearrangements in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia. in International Journal of Laboratory Hematology. 2023;45(6).
doi:doi.org/10.1111/ijlh.14200 .

Kačanski, Nataša, Kolarović, Jovanka, Kostić, Tatjana, Marjanović, Irena, Janić, Dragana, Pavlović, Sonja, Karan-Đurašević, Teodora, "Presence of leukemic clone-specific immunoglobulin heavy chain rearrangements in neonatal blood spots of children with B-cell precursor acute lymphoblastic leukemia" in International Journal of Laboratory Hematology, 45, no. 6 (2023),
https://doi.org/doi.org/10.1111/ijlh.14200 . .

TY  - JOUR
AU  - Janić, Dragana
AU  - Perić, Jelena
AU  - Karan-Đurašević, Teodora
AU  - Kostić, Tatjana
AU  - Marjanović, Irena
AU  - Stanić, Bojana
AU  - Pejanović, Nadja
AU  - Dokmanović, Lidija
AU  - Lazić, Jelena
AU  - Krstovski, Nada
AU  - Virijević, Marijana
AU  - Tomin, Dragica
AU  - Vidović, Ana
AU  - Suvajdžić-Vuković, Nada
AU  - Pavlović, Sonja
AU  - Tošić, Nataša
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1303
AB  - lt b gt Uvod: lt /b gt  Akutna limfoblastna leukemija (ALL) je najčešće maligno oboljenje kod dece, dok je kod odraslih njena učestalost mnogo niža. U današnjoj kliničkoj praksi kao najvažnije metode stratifikacije pacijenata u određene grupe rizika koriste se metode identifikacije citogenetičkih aberacija i malog broja molekulanih markera. Tehnologija sekvenciranja nove generacije (SNG) obezbeđuje veliku količinu podataka koji doprinose razjašnjavanju mutacionog profila dečje (dALL) i adultne ALL (aALL).  lt b gt Metode: lt /b gt  Uzorci DNK iz 34 dALL i aALL pacijenata analizirani su primenom SNG ciljanog sekvenciranja ("TruSeq Amplicon Cancer Panel - TSACP") kojim se sekvenciraju "hotspot" mutacije u 48 gena povezanih sa kancerom.  lt b gt Rezultati: lt /b gt  Identifikovano je ukupno 330 varijanti u kodirajućim regionima, od kojih je samo 95 njih za posledicu imalo potencijalnu promenu u proteinu. Posmatrano kod pojedinačnih pacijenata, detektovane mutacije su pretežno remetile Ras/RTK signalni put (STK11, KIT, MET, NRAS, KRAS, PTEN). Pored toga, identifikovano je 5 pacijenata sa istom mutacijom u HNF1A genu, koja je uzrokovala poremećaje u Wnt i Notch signalnom putu. Kod dva pa cijenta otkrivene su varijante u NOTCH1 genu. Nije detektovano istovremeno prisustvo varijanti u HNF1A i NOTCH1 genu, dok su geni uključeni u Ras/RTK signalni put pokazali tendenciju ka akumuliranju mutacija.  lt b gt Zaključak: lt /b gt  Naši rezultati pokazuju da ALL sadrži Mali broj mutacija, bez značajnih razlika između dALL i aALL (medijana po pacijentu 2 odnosno 3). Detektovane mutacije izazivaju poremećaje u nekoliko ključnih signalnih puteva, prvenstveno Ras/RTK kaskade. Ova studija doprinosi ukupnom znanju o mutacionom profilu ALL, što vodi ka boljem razumijevanju molekularne osnove ovog oboljenja.
AB  - lt b gt Background: lt /b gt  Acute lymphoblastic leukemia (ALL) is the most common cancer in children, whereas it is less common in adults. Identification of cytogenetic aberrations and a small number of molecular abnormalities are still the most important risk and therapy stratification methods in clinical practice today. Next generation sequencing (NGS) technology provides a large amount of data contributing to elucidation of mutational landscape of childhood (cALL) and adult ALL (aALL).  lt b gt Methods: lt /b gt  We analyzed DNA samples from 34 cALL and aALL patients, using NGS targeted sequencing TruSeq Amplicon - Cancer Panel (TSACP) which targets mutational hotspots in 48 cancer related genes.  lt b gt Results: lt /b gt  We identified a total of 330 variants in the coding regions, out of which only 95 were potentially protein-changing. Observed in individual patients, detected mutations predominantly disrupted Ras/RTK pathway (STK11, KIT, MET, NRAS, KRAS, PTEN). Additionally, we identified 5 patients with the same mutation in HNF1A gene, disrupting both Wnt and Notch signaling pathway. In two patients we detected variants in NOTCH1 gene. HNF1A and NOTCH1 variants were mutually exclusive, while genes involved in Ras/RTK pathway exhibit a tendency of mutation accumulation.  lt b gt Conclusions: lt /b gt  Our results showed that ALL contains low number of mutations, without significant differences between cALL and aALL (median per patient 2 and 3, respectively). Detected mutations affect few key signaling pathways, primarily Ras/RTK cascade. This study contributes to knowledge of ALL mutational landscape, leading to better understanding of molecular basis of this disease.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom
T1  - Application of targeted next generation sequencing for the mutational profiling of patients with acute lymphoblastic leukemia
EP  - 82
IS  - 1
SP  - 72
VL  - 39
DO  - 10.2478/jomb-2019-0017
ER  - 

@article{
author = "Janić, Dragana and Perić, Jelena and Karan-Đurašević, Teodora and Kostić, Tatjana and Marjanović, Irena and Stanić, Bojana and Pejanović, Nadja and Dokmanović, Lidija and Lazić, Jelena and Krstovski, Nada and Virijević, Marijana and Tomin, Dragica and Vidović, Ana and Suvajdžić-Vuković, Nada and Pavlović, Sonja and Tošić, Nataša",
year = "2020",
abstract = "lt b gt Uvod: lt /b gt  Akutna limfoblastna leukemija (ALL) je najčešće maligno oboljenje kod dece, dok je kod odraslih njena učestalost mnogo niža. U današnjoj kliničkoj praksi kao najvažnije metode stratifikacije pacijenata u određene grupe rizika koriste se metode identifikacije citogenetičkih aberacija i malog broja molekulanih markera. Tehnologija sekvenciranja nove generacije (SNG) obezbeđuje veliku količinu podataka koji doprinose razjašnjavanju mutacionog profila dečje (dALL) i adultne ALL (aALL).  lt b gt Metode: lt /b gt  Uzorci DNK iz 34 dALL i aALL pacijenata analizirani su primenom SNG ciljanog sekvenciranja ("TruSeq Amplicon Cancer Panel - TSACP") kojim se sekvenciraju "hotspot" mutacije u 48 gena povezanih sa kancerom.  lt b gt Rezultati: lt /b gt  Identifikovano je ukupno 330 varijanti u kodirajućim regionima, od kojih je samo 95 njih za posledicu imalo potencijalnu promenu u proteinu. Posmatrano kod pojedinačnih pacijenata, detektovane mutacije su pretežno remetile Ras/RTK signalni put (STK11, KIT, MET, NRAS, KRAS, PTEN). Pored toga, identifikovano je 5 pacijenata sa istom mutacijom u HNF1A genu, koja je uzrokovala poremećaje u Wnt i Notch signalnom putu. Kod dva pa cijenta otkrivene su varijante u NOTCH1 genu. Nije detektovano istovremeno prisustvo varijanti u HNF1A i NOTCH1 genu, dok su geni uključeni u Ras/RTK signalni put pokazali tendenciju ka akumuliranju mutacija.  lt b gt Zaključak: lt /b gt  Naši rezultati pokazuju da ALL sadrži Mali broj mutacija, bez značajnih razlika između dALL i aALL (medijana po pacijentu 2 odnosno 3). Detektovane mutacije izazivaju poremećaje u nekoliko ključnih signalnih puteva, prvenstveno Ras/RTK kaskade. Ova studija doprinosi ukupnom znanju o mutacionom profilu ALL, što vodi ka boljem razumijevanju molekularne osnove ovog oboljenja., lt b gt Background: lt /b gt  Acute lymphoblastic leukemia (ALL) is the most common cancer in children, whereas it is less common in adults. Identification of cytogenetic aberrations and a small number of molecular abnormalities are still the most important risk and therapy stratification methods in clinical practice today. Next generation sequencing (NGS) technology provides a large amount of data contributing to elucidation of mutational landscape of childhood (cALL) and adult ALL (aALL).  lt b gt Methods: lt /b gt  We analyzed DNA samples from 34 cALL and aALL patients, using NGS targeted sequencing TruSeq Amplicon - Cancer Panel (TSACP) which targets mutational hotspots in 48 cancer related genes.  lt b gt Results: lt /b gt  We identified a total of 330 variants in the coding regions, out of which only 95 were potentially protein-changing. Observed in individual patients, detected mutations predominantly disrupted Ras/RTK pathway (STK11, KIT, MET, NRAS, KRAS, PTEN). Additionally, we identified 5 patients with the same mutation in HNF1A gene, disrupting both Wnt and Notch signaling pathway. In two patients we detected variants in NOTCH1 gene. HNF1A and NOTCH1 variants were mutually exclusive, while genes involved in Ras/RTK pathway exhibit a tendency of mutation accumulation.  lt b gt Conclusions: lt /b gt  Our results showed that ALL contains low number of mutations, without significant differences between cALL and aALL (median per patient 2 and 3, respectively). Detected mutations affect few key signaling pathways, primarily Ras/RTK cascade. This study contributes to knowledge of ALL mutational landscape, leading to better understanding of molecular basis of this disease.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom, Application of targeted next generation sequencing for the mutational profiling of patients with acute lymphoblastic leukemia",
pages = "82-72",
number = "1",
volume = "39",
doi = "10.2478/jomb-2019-0017"
}

Janić, D., Perić, J., Karan-Đurašević, T., Kostić, T., Marjanović, I., Stanić, B., Pejanović, N., Dokmanović, L., Lazić, J., Krstovski, N., Virijević, M., Tomin, D., Vidović, A., Suvajdžić-Vuković, N., Pavlović, S.,& Tošić, N.. (2020). Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 39(1), 72-82.
https://doi.org/10.2478/jomb-2019-0017

Janić D, Perić J, Karan-Đurašević T, Kostić T, Marjanović I, Stanić B, Pejanović N, Dokmanović L, Lazić J, Krstovski N, Virijević M, Tomin D, Vidović A, Suvajdžić-Vuković N, Pavlović S, Tošić N. Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom. in Journal of Medical Biochemistry. 2020;39(1):72-82.
doi:10.2478/jomb-2019-0017 .

Janić, Dragana, Perić, Jelena, Karan-Đurašević, Teodora, Kostić, Tatjana, Marjanović, Irena, Stanić, Bojana, Pejanović, Nadja, Dokmanović, Lidija, Lazić, Jelena, Krstovski, Nada, Virijević, Marijana, Tomin, Dragica, Vidović, Ana, Suvajdžić-Vuković, Nada, Pavlović, Sonja, Tošić, Nataša, "Primena ciljanog sekvenciranja nove generacije u analizi mutacionog profila pacijenata sa akutnom limfoblastnom leukemijom" in Journal of Medical Biochemistry, 39, no. 1 (2020):72-82,
https://doi.org/10.2478/jomb-2019-0017 . .

TY  - JOUR
AU  - Kotur, Nikola
AU  - Lazić, Jelena
AU  - Ristivojević, Bojan
AU  - Stanković, Biljana
AU  - Gašić, Vladimir
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Milosević, Goran
AU  - Janić, Dragana
AU  - Zukić, Branka
AU  - Pavlović, Sonja
PY  - 2020
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1322
AB  - Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.
PB  - MDPI, Basel
T2  - Genes
T1  - Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment
IS  - 4
VL  - 11
DO  - 10.3390/genes11040468
ER  - 

@article{
author = "Kotur, Nikola and Lazić, Jelena and Ristivojević, Bojan and Stanković, Biljana and Gašić, Vladimir and Dokmanović, Lidija and Krstovski, Nada and Milosević, Goran and Janić, Dragana and Zukić, Branka and Pavlović, Sonja",
year = "2020",
abstract = "Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.",
publisher = "MDPI, Basel",
journal = "Genes",
title = "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment",
number = "4",
volume = "11",
doi = "10.3390/genes11040468"
}

Kotur, N., Lazić, J., Ristivojević, B., Stanković, B., Gašić, V., Dokmanović, L., Krstovski, N., Milosević, G., Janić, D., Zukić, B.,& Pavlović, S.. (2020). Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes
MDPI, Basel., 11(4).
https://doi.org/10.3390/genes11040468

Kotur N, Lazić J, Ristivojević B, Stanković B, Gašić V, Dokmanović L, Krstovski N, Milosević G, Janić D, Zukić B, Pavlović S. Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes. 2020;11(4).
doi:10.3390/genes11040468 .

Kotur, Nikola, Lazić, Jelena, Ristivojević, Bojan, Stanković, Biljana, Gašić, Vladimir, Dokmanović, Lidija, Krstovski, Nada, Milosević, Goran, Janić, Dragana, Zukić, Branka, Pavlović, Sonja, "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment" in Genes, 11, no. 4 (2020),
https://doi.org/10.3390/genes11040468 . .

TY  - JOUR
AU  - Gašić, Vladimir
AU  - Stanković, Biljana
AU  - Zukić, Branka
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Milošević, Goran
AU  - Lucafò, Marianna
AU  - Stocco, Gabriele
AU  - Decorti, Giuliana
AU  - Pavlović, Sonja
AU  - Kotur, Nikola
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1269
AB  - Uvod: Ekspresija duge nekodirajuće RNK G AS5 je izme - njena u mnogim kancerima zbog njene uloge u apoptozi i inhibiciji rasta ćelije. G AS5 interaguje sa glukokortikoidnim receptorom, što je čini potencijalnim farmakotranskripcionim markerom značajnim za glukokortikoidnu terapiju. Naš cilj u ovoj studiji je bio da analiziramo ekspresiju GAS5 tokom indukcione terapije kod dečje akutne limfoblastne leukemije (ALL), u kojoj se koriste glukokortikoidni lekovi, i da te rezultate povežemo sa odgovorom na terapiju. Metode: Nivo ekspresije G AS5 u mononuklearnim ćelijama periferne krvi izolovanih od 29 dece obolelih od ALL, određen je metodologijom RT-qPCR, i to u momentu dijagnoze, 15. i 33. dana indukcione terapije. Rezultati: Naši rezultati su pokazali da postoje interindivi - dualne razlike u ekspresiji GAS5 kod pacijenata, i to u svim analiziranim tačkama. Kod svakog ALL pacijenta GAS5 ekspresija je 15. dana bila visa u odnosu na ekspresiju u momentu dijagnoze (p  lt  0,0005). Nivo ekspresije GAS5 je 33. dana bio niži u poređenju sa 15. danom (p  lt  0,0005), ali je i dalje bio značajno visi u odnosu na momenat dijagnoze kod većine pacijenata (p = 0,001). Pacijenti čiji je broj blasta u perifernoj krvi 8. dana bio ispod 100 po mikrolitru periferne krvi, imali su viši nivo ekspresije GAS5 (p = 0,016) i niži odnos ekspresija merenih 15. dana i u momentu dijagnoze (p = 0,009). Zaključak: Nasi rezultati ukazuju da bi nivo ekspresije GAS5 mogao da bude marker terapijskog odgovora u indukcionoj terapiji kod dece obolele od ALL.
AB  - Background: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing G AS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods: G AS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. Results: Our results have shown interindividual differences in G AS5 expression at all time points. For each ALL patient, G A S5 expression was higher on day 15 in comparison to its level at diagnosis (p lt 0.0005). On day 33, the level of G A S5 expression decreased in comparison with day 15 (p lt 0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per mL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije
T1  - Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia
EP  - 298
IS  - 3
SP  - 292
VL  - 38
DO  - 10.2478/jomb-2018-0038
ER  - 

@article{
author = "Gašić, Vladimir and Stanković, Biljana and Zukić, Branka and Janić, Dragana and Dokmanović, Lidija and Krstovski, Nada and Lazić, Jelena and Milošević, Goran and Lucafò, Marianna and Stocco, Gabriele and Decorti, Giuliana and Pavlović, Sonja and Kotur, Nikola",
year = "2019",
abstract = "Uvod: Ekspresija duge nekodirajuće RNK G AS5 je izme - njena u mnogim kancerima zbog njene uloge u apoptozi i inhibiciji rasta ćelije. G AS5 interaguje sa glukokortikoidnim receptorom, što je čini potencijalnim farmakotranskripcionim markerom značajnim za glukokortikoidnu terapiju. Naš cilj u ovoj studiji je bio da analiziramo ekspresiju GAS5 tokom indukcione terapije kod dečje akutne limfoblastne leukemije (ALL), u kojoj se koriste glukokortikoidni lekovi, i da te rezultate povežemo sa odgovorom na terapiju. Metode: Nivo ekspresije G AS5 u mononuklearnim ćelijama periferne krvi izolovanih od 29 dece obolelih od ALL, određen je metodologijom RT-qPCR, i to u momentu dijagnoze, 15. i 33. dana indukcione terapije. Rezultati: Naši rezultati su pokazali da postoje interindivi - dualne razlike u ekspresiji GAS5 kod pacijenata, i to u svim analiziranim tačkama. Kod svakog ALL pacijenta GAS5 ekspresija je 15. dana bila visa u odnosu na ekspresiju u momentu dijagnoze (p  lt  0,0005). Nivo ekspresije GAS5 je 33. dana bio niži u poređenju sa 15. danom (p  lt  0,0005), ali je i dalje bio značajno visi u odnosu na momenat dijagnoze kod većine pacijenata (p = 0,001). Pacijenti čiji je broj blasta u perifernoj krvi 8. dana bio ispod 100 po mikrolitru periferne krvi, imali su viši nivo ekspresije GAS5 (p = 0,016) i niži odnos ekspresija merenih 15. dana i u momentu dijagnoze (p = 0,009). Zaključak: Nasi rezultati ukazuju da bi nivo ekspresije GAS5 mogao da bude marker terapijskog odgovora u indukcionoj terapiji kod dece obolele od ALL., Background: Long non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, GAS5 interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing G AS5 expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response. Methods: G AS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology. Results: Our results have shown interindividual differences in G AS5 expression at all time points. For each ALL patient, G A S5 expression was higher on day 15 in comparison to its level at diagnosis (p lt 0.0005). On day 33, the level of G A S5 expression decreased in comparison with day 15 (p lt 0.0005), but it was still significantly higher than at diagnosis for the majority of patients (p=0.001). Patients whose number of blasts on day 8 was below 100 per mL of peripheral blood had a higher GAS5 expression at diagnosis (p=0.016), and lower ratio day 15/diagnosis (p=0.009). Conclusions: Our results suggest that the expression level of GAS5 could be a potential marker of therapy response in remission induction therapy of childhood ALL.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije, Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia",
pages = "298-292",
number = "3",
volume = "38",
doi = "10.2478/jomb-2018-0038"
}

Gašić, V., Stanković, B., Zukić, B., Janić, D., Dokmanović, L., Krstovski, N., Lazić, J., Milošević, G., Lucafò, M., Stocco, G., Decorti, G., Pavlović, S.,& Kotur, N.. (2019). Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 38(3), 292-298.
https://doi.org/10.2478/jomb-2018-0038

Gašić V, Stanković B, Zukić B, Janić D, Dokmanović L, Krstovski N, Lazić J, Milošević G, Lucafò M, Stocco G, Decorti G, Pavlović S, Kotur N. Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije. in Journal of Medical Biochemistry. 2019;38(3):292-298.
doi:10.2478/jomb-2018-0038 .

Gašić, Vladimir, Stanković, Biljana, Zukić, Branka, Janić, Dragana, Dokmanović, Lidija, Krstovski, Nada, Lazić, Jelena, Milošević, Goran, Lucafò, Marianna, Stocco, Gabriele, Decorti, Giuliana, Pavlović, Sonja, Kotur, Nikola, "Ekspresioni obrazac duge nekodirajuće RNK growth arrest specific 5 u fazi indukcije u terapiji dečje akutne limfoblastne leukemije" in Journal of Medical Biochemistry, 38, no. 3 (2019):292-298,
https://doi.org/10.2478/jomb-2018-0038 . .

TY  - JOUR
AU  - Milosević, Goran
AU  - Kotur, Nikola
AU  - Lazić, Jelena
AU  - Krstovski, Nada
AU  - Stanković, Biljana
AU  - Zukić, Branka
AU  - Janić, Dragana
AU  - Jurisić, Vladimir
AU  - Pavlović, Sonja
AU  - Dokmanović, Lidija
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1235
AB  - Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680, -675, -556, -464, -317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants.
PB  - Balkan Union of Oncology (B.U.ON.)
T2  - Journal of Buon
T1  - Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia
EP  - 2083
IS  - 5
SP  - 2075
VL  - 24
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1235
ER  - 

@article{
author = "Milosević, Goran and Kotur, Nikola and Lazić, Jelena and Krstovski, Nada and Stanković, Biljana and Zukić, Branka and Janić, Dragana and Jurisić, Vladimir and Pavlović, Sonja and Dokmanović, Lidija",
year = "2019",
abstract = "Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680, -675, -556, -464, -317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants.",
publisher = "Balkan Union of Oncology (B.U.ON.)",
journal = "Journal of Buon",
title = "Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia",
pages = "2083-2075",
number = "5",
volume = "24",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1235"
}

Milosević, G., Kotur, N., Lazić, J., Krstovski, N., Stanković, B., Zukić, B., Janić, D., Jurisić, V., Pavlović, S.,& Dokmanović, L.. (2019). Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia. in Journal of Buon
Balkan Union of Oncology (B.U.ON.)., 24(5), 2075-2083.
https://hdl.handle.net/21.15107/rcub_imagine_1235

Milosević G, Kotur N, Lazić J, Krstovski N, Stanković B, Zukić B, Janić D, Jurisić V, Pavlović S, Dokmanović L. Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia. in Journal of Buon. 2019;24(5):2075-2083.
https://hdl.handle.net/21.15107/rcub_imagine_1235 .

Milosević, Goran, Kotur, Nikola, Lazić, Jelena, Krstovski, Nada, Stanković, Biljana, Zukić, Branka, Janić, Dragana, Jurisić, Vladimir, Pavlović, Sonja, Dokmanović, Lidija, "Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia" in Journal of Buon, 24, no. 5 (2019):2075-2083,
https://hdl.handle.net/21.15107/rcub_imagine_1235 .

TY  - JOUR
AU  - Rodić, Predrag
AU  - Lakočević, Milan
AU  - Pavlović, Sonja
AU  - Karan-Đurašević, Teodora
AU  - Kostić, Tatjana
AU  - Suvajdžić-Vuković, Nada
AU  - Šumarac, Zorica
AU  - Petakov, Milan
AU  - Janić, Dragana
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1113
AB  - Uvod: Nekoliko studija u literaturi navode dokaze o povećanoj incidenci hematoloških komplikacija u bolesnika sa Gošeovom bolešću, uključujući monoklonsku i poliklonsku gamapatiju i hematološke malignitete, a posebno multipli mijelom. Metode: Određivana je serumska koncentracija imunoglobulina kao i rearanžman gena za teški lanac imunoglobulina - IGH, PCR analizom. Klonalni PCR produkti su direktno sekvencirani i analizirani koristeći adekvatne alate i baze podataka. Monoklonski proteini seruma su detektovani i identifikovani metodom elektroforeze. Rezultati: Među 27 bolesnika, klonalni IGH rearanžman je otkriven kod osmoro, od kojih je petoro imalo i monot klonski protein u serumu. Hipergamaglobulinemija je otkrivena u 9/27 bolesnika. Podaci o praćenju za 17 bolesnika su pokazali da je klonalni rearanžman ostao isti u četiri bolesnika, dok je u jednog bolesnika iščezao tokom perioda praćenja. Preostalih 12/17 bolesnika nisu imali klonalni IGH rearanžman niti su ga stekli nakon perioda praćenja. Zaključak: Iako klonska ekspanzija može da nastane relativno rano u toku Gošeove bolesti, barem sudeći prema rearanžmanu IGH gena, detektovani klonovi mogu biti tranzitorni. Pažljivo kliničko praćenje ovih bolesnika je obavezno, uključujući i nadzor nad limfoidnim neoplazmama, posebno multiplim mijelomom.
AB  - Background: Several studies support the evidence of increased incidence of hematological complications in Gaucher disease including monoclonal and polyclonal gammopathies and blood malignancies, especially multiple myeloma. Methods: Serum concentrations of immunoglobulins and PCR analysis of the IGH gene rearrangements were performed. The clonal PCR products were directly sequenced and analyzed with the appropriate database and tools. Serum monoclonal proteins were detected and identified by electrophoresis. Results: Among 27 Gaucher patients, clonal IGH rearrangement was discovered in eight, with 5/8 having also serum monoclonal protein. Elevated immunoglobulins were detected in 9/27 patients. Follow-up data for 17 patients showed that the clonal rearrangement remained the same in four of them, however, in one patient it disappeared after the follow-up period. The remaining 12/17 patients were without previous IGH clonal rearrangement and remained so after the follow-up. Conclusions: Although clonal expansion may occur relatively early in the disease course, at least judging by the IGH gene rearrangements in Gaucher patients, the detected clones may be transient. A careful clinical follow-up in these patients is mandatory, including monitoring for lymphoid neoplasms, especially multiple myeloma.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Rearanžmani gena za teški lanac imunoglobulina u bolesnika sa Gošeovom bolešću
T1  - Immunoglobulin heavy chain gene rearrangements in patients with Gaucher disease
EP  - 312
IS  - 3
SP  - 307
VL  - 37
DO  - 10.1515/jomb-2017-0061
ER  - 

@article{
author = "Rodić, Predrag and Lakočević, Milan and Pavlović, Sonja and Karan-Đurašević, Teodora and Kostić, Tatjana and Suvajdžić-Vuković, Nada and Šumarac, Zorica and Petakov, Milan and Janić, Dragana",
year = "2018",
abstract = "Uvod: Nekoliko studija u literaturi navode dokaze o povećanoj incidenci hematoloških komplikacija u bolesnika sa Gošeovom bolešću, uključujući monoklonsku i poliklonsku gamapatiju i hematološke malignitete, a posebno multipli mijelom. Metode: Određivana je serumska koncentracija imunoglobulina kao i rearanžman gena za teški lanac imunoglobulina - IGH, PCR analizom. Klonalni PCR produkti su direktno sekvencirani i analizirani koristeći adekvatne alate i baze podataka. Monoklonski proteini seruma su detektovani i identifikovani metodom elektroforeze. Rezultati: Među 27 bolesnika, klonalni IGH rearanžman je otkriven kod osmoro, od kojih je petoro imalo i monot klonski protein u serumu. Hipergamaglobulinemija je otkrivena u 9/27 bolesnika. Podaci o praćenju za 17 bolesnika su pokazali da je klonalni rearanžman ostao isti u četiri bolesnika, dok je u jednog bolesnika iščezao tokom perioda praćenja. Preostalih 12/17 bolesnika nisu imali klonalni IGH rearanžman niti su ga stekli nakon perioda praćenja. Zaključak: Iako klonska ekspanzija može da nastane relativno rano u toku Gošeove bolesti, barem sudeći prema rearanžmanu IGH gena, detektovani klonovi mogu biti tranzitorni. Pažljivo kliničko praćenje ovih bolesnika je obavezno, uključujući i nadzor nad limfoidnim neoplazmama, posebno multiplim mijelomom., Background: Several studies support the evidence of increased incidence of hematological complications in Gaucher disease including monoclonal and polyclonal gammopathies and blood malignancies, especially multiple myeloma. Methods: Serum concentrations of immunoglobulins and PCR analysis of the IGH gene rearrangements were performed. The clonal PCR products were directly sequenced and analyzed with the appropriate database and tools. Serum monoclonal proteins were detected and identified by electrophoresis. Results: Among 27 Gaucher patients, clonal IGH rearrangement was discovered in eight, with 5/8 having also serum monoclonal protein. Elevated immunoglobulins were detected in 9/27 patients. Follow-up data for 17 patients showed that the clonal rearrangement remained the same in four of them, however, in one patient it disappeared after the follow-up period. The remaining 12/17 patients were without previous IGH clonal rearrangement and remained so after the follow-up. Conclusions: Although clonal expansion may occur relatively early in the disease course, at least judging by the IGH gene rearrangements in Gaucher patients, the detected clones may be transient. A careful clinical follow-up in these patients is mandatory, including monitoring for lymphoid neoplasms, especially multiple myeloma.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Rearanžmani gena za teški lanac imunoglobulina u bolesnika sa Gošeovom bolešću, Immunoglobulin heavy chain gene rearrangements in patients with Gaucher disease",
pages = "312-307",
number = "3",
volume = "37",
doi = "10.1515/jomb-2017-0061"
}

Rodić, P., Lakočević, M., Pavlović, S., Karan-Đurašević, T., Kostić, T., Suvajdžić-Vuković, N., Šumarac, Z., Petakov, M.,& Janić, D.. (2018). Rearanžmani gena za teški lanac imunoglobulina u bolesnika sa Gošeovom bolešću. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 37(3), 307-312.
https://doi.org/10.1515/jomb-2017-0061

Rodić P, Lakočević M, Pavlović S, Karan-Đurašević T, Kostić T, Suvajdžić-Vuković N, Šumarac Z, Petakov M, Janić D. Rearanžmani gena za teški lanac imunoglobulina u bolesnika sa Gošeovom bolešću. in Journal of Medical Biochemistry. 2018;37(3):307-312.
doi:10.1515/jomb-2017-0061 .

Rodić, Predrag, Lakočević, Milan, Pavlović, Sonja, Karan-Đurašević, Teodora, Kostić, Tatjana, Suvajdžić-Vuković, Nada, Šumarac, Zorica, Petakov, Milan, Janić, Dragana, "Rearanžmani gena za teški lanac imunoglobulina u bolesnika sa Gošeovom bolešću" in Journal of Medical Biochemistry, 37, no. 3 (2018):307-312,
https://doi.org/10.1515/jomb-2017-0061 . .

TY  - JOUR
AU  - Dokmanović, Lidija
AU  - Milošević, Goran
AU  - Perić, Jelena
AU  - Tošić, Nataša
AU  - Krstovski, Nada
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1131
AB  - Uvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL.
AB  - Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece
T1  - Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia
EP  - 411
IS  - 7-8
SP  - 407
VL  - 146
DO  - 10.2298/SARH171003194D
ER  - 

@article{
author = "Dokmanović, Lidija and Milošević, Goran and Perić, Jelena and Tošić, Nataša and Krstovski, Nada and Janić, Dragana and Pavlović, Sonja",
year = "2018",
abstract = "Uvod/Cilj Sekvenciranje nove generacije (SNG) omogućilo je genomsko profilisanje svakog bolesnika. Nova saznanja u oblasti farmakogenomike omogućavaju primenu podataka dobijenih ovom metodom u cilju otkrivanja novih mogućih genetičkih markera za ciljanu terapiju mnogih, posebno malignih bolesti. Cilj ovog istraživanja je bio da se primenom SNG odre- di genetski profil akutne limfoblastne leukemije (ALL) kod dece u cilju procene mogućih molekularnih meta za ciljanu terapiju. Metode Analizirali smo DNK uzorke 17 bolesnika obolelih od ALL dečjeg doba koristeći ciljano SNG. Napredne bioinformatičke metode su korišćene da identifikuju nove mutacije u analiziranim genima i da predvide njihov uticaj i farmakogenomski potencijal. Rezultati Identifikovali smo devet genskih varijanti koje do sada nisu opisane u relevantnim bazama podataka. U navedenim varijantama identifikovane su dve 'besmislene' varijante, ABL1 p.Q252* i AKT1 p.W22*, jedna varijanta koja pomera okvir čitanja, STK11 p.G257fs*28, i šest nesinonimnih varijanti. Kreirali smo trodimenzionalni model za četiri proteina koji bi bili produkt novih nesinonimnih varijanti. Analizirali smo farmakogenomski potencijal svake varijante i otkrili da su dve, STK11 c.1023G gt T/ p.L341F i ERBB2 c.2341C gt T/ p.R781W, mogući kandidati za ciljanu terapiju. Zaključak Nove varijante otkrivene u ovoj studiji pripa- daju uglavnom genima povezanim sa Ras signalnim putem, koji je često zahvaćen mutacijama u ALL kod dece. Farmakogenomsko profilisanje svake dečje ALL biće nezamenljivo za nove terapijske pristupe. Detekcija i inicijalna analiza novih genskih varijanti, koja je predstavljena u ovoj studiji, postaće standardna procedura za dizajniranje i razvoj individualizovane terapije za decu obolelu od ALL., Introduction/Objective Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G gt T/ p.L341F and ERBB2 c.2341C gt T/ p.R781W, are suitable candidates for targeted therapy. Conclusion Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece, Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia",
pages = "411-407",
number = "7-8",
volume = "146",
doi = "10.2298/SARH171003194D"
}

Dokmanović, L., Milošević, G., Perić, J., Tošić, N., Krstovski, N., Janić, D.,& Pavlović, S.. (2018). Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 146(7-8), 407-411.
https://doi.org/10.2298/SARH171003194D

Dokmanović L, Milošević G, Perić J, Tošić N, Krstovski N, Janić D, Pavlović S. Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece. in Srpski arhiv za celokupno lekarstvo. 2018;146(7-8):407-411.
doi:10.2298/SARH171003194D .

Dokmanović, Lidija, Milošević, Goran, Perić, Jelena, Tošić, Nataša, Krstovski, Nada, Janić, Dragana, Pavlović, Sonja, "Sekvenciranje nove generacije kao metoda za farmakogenomsko profilisanje - devet novih potencijalnih genetičkih markera za ciljanu terapiju akutne limfoblastne leukemije kod dece" in Srpski arhiv za celokupno lekarstvo, 146, no. 7-8 (2018):407-411,
https://doi.org/10.2298/SARH171003194D . .

TY  - JOUR
AU  - Milošević, Goran
AU  - Kotur, Nikola
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Zukić, Branka
AU  - Stanković, Biljana
AU  - Janić, Dragana
AU  - Katsila, Theodora
AU  - Patrinos, George P.
AU  - Pavlović, Sonja
AU  - Dokmanović, Lidija
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1116
AB  - Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije.
AB  - Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije
T1  - Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia
EP  - 327
IS  - 3
SP  - 320
VL  - 37
DO  - 10.1515/jomb-2017-0060
ER  - 

@article{
author = "Milošević, Goran and Kotur, Nikola and Krstovski, Nada and Lazić, Jelena and Zukić, Branka and Stanković, Biljana and Janić, Dragana and Katsila, Theodora and Patrinos, George P. and Pavlović, Sonja and Dokmanović, Lidija",
year = "2018",
abstract = "Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije., Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije, Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia",
pages = "327-320",
number = "3",
volume = "37",
doi = "10.1515/jomb-2017-0060"
}

Milošević, G., Kotur, N., Krstovski, N., Lazić, J., Zukić, B., Stanković, B., Janić, D., Katsila, T., Patrinos, G. P., Pavlović, S.,& Dokmanović, L.. (2018). Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 37(3), 320-327.
https://doi.org/10.1515/jomb-2017-0060

Milošević G, Kotur N, Krstovski N, Lazić J, Zukić B, Stanković B, Janić D, Katsila T, Patrinos GP, Pavlović S, Dokmanović L. Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry. 2018;37(3):320-327.
doi:10.1515/jomb-2017-0060 .

Milošević, Goran, Kotur, Nikola, Krstovski, Nada, Lazić, Jelena, Zukić, Branka, Stanković, Biljana, Janić, Dragana, Katsila, Theodora, Patrinos, George P., Pavlović, Sonja, Dokmanović, Lidija, "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije" in Journal of Medical Biochemistry, 37, no. 3 (2018):320-327,
https://doi.org/10.1515/jomb-2017-0060 . .

TY  - JOUR
AU  - Gašić, Vladimir
AU  - Zukić, Branka
AU  - Stanković, Biljana
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Lazić, Jelena
AU  - Krstovski, Nada
AU  - Dolzan, Vita
AU  - Jazbec, Janez
AU  - Pavlović, Sonja
AU  - Kotur, Nikola
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1099
AB  - Background. Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods. Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTPI (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results. Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the noncarriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rsl 138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions. Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.
PB  - Walter De Gruyter Gmbh, Berlin
T2  - Radiology and Oncology
T1  - Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia
EP  - 306
IS  - 3
SP  - 296
VL  - 52
DO  - 10.2478/raon-2018-0034
ER  - 

@article{
author = "Gašić, Vladimir and Zukić, Branka and Stanković, Biljana and Janić, Dragana and Dokmanović, Lidija and Lazić, Jelena and Krstovski, Nada and Dolzan, Vita and Jazbec, Janez and Pavlović, Sonja and Kotur, Nikola",
year = "2018",
abstract = "Background. Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods. Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTPI (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology. The marker of GC response was blast count per microliter of peripheral blood on treatment day 8. We carried out analysis in which cut-off value for GC response was 1000 (according to Berlin-Frankfurt-Munster [BFM] protocol), as well as 100 or 0 blasts per microliter. Results. Carriers of rare NR3C1 rs6198 GG genotype were more likely to have blast count over 1000, than the noncarriers (p = 0.030). NR3C1 CAA (rs33389-rs33388-rs6198) haplotype was associated with blast number below 1000 (p = 0.030). GSTP1 GC haplotype carriers were more likely to have blast number below 1000 (p = 0.036), below 100 (p = 0.028) and to be blast negative (p = 0.054), while GSTP1 GT haplotype and rsl 138272 T allele carriers were more likely to be blasts positive (p = 0.034 and p = 0.024, respectively). ABCB1 CGT (rs1128503-rs2032582-rs1045642) haplotype carriers were more likely to be blast positive (p = 0.018). Conclusions. Our results have shown that NR3C1 rs6198 variant and GSTP1 rs1695-rs1138272 haplotype are the most promising pharmacogenomic markers of GC response in ALL patients.",
publisher = "Walter De Gruyter Gmbh, Berlin",
journal = "Radiology and Oncology",
title = "Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia",
pages = "306-296",
number = "3",
volume = "52",
doi = "10.2478/raon-2018-0034"
}

Gašić, V., Zukić, B., Stanković, B., Janić, D., Dokmanović, L., Lazić, J., Krstovski, N., Dolzan, V., Jazbec, J., Pavlović, S.,& Kotur, N.. (2018). Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia. in Radiology and Oncology
Walter De Gruyter Gmbh, Berlin., 52(3), 296-306.
https://doi.org/10.2478/raon-2018-0034

Gašić V, Zukić B, Stanković B, Janić D, Dokmanović L, Lazić J, Krstovski N, Dolzan V, Jazbec J, Pavlović S, Kotur N. Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia. in Radiology and Oncology. 2018;52(3):296-306.
doi:10.2478/raon-2018-0034 .

Gašić, Vladimir, Zukić, Branka, Stanković, Biljana, Janić, Dragana, Dokmanović, Lidija, Lazić, Jelena, Krstovski, Nada, Dolzan, Vita, Jazbec, Janez, Pavlović, Sonja, Kotur, Nikola, "Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia" in Radiology and Oncology, 52, no. 3 (2018):296-306,
https://doi.org/10.2478/raon-2018-0034 . .

TY  - JOUR
AU  - Lazić, Jelena
AU  - Kotur, Nikola
AU  - Krstovski, Nada
AU  - Dokmanović, Lidija
AU  - Zukić, Branka
AU  - Predojević-Samardzić, Jelica
AU  - Zivotić, Maja
AU  - Milosević, Goran
AU  - Dorić, Milica
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2017
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1080
AB  - Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C gt T and MTHFR c.1298A gt C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A gt C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C gt T nor MTHFR c.1298A gt C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.
PB  - Srpsko biološko društvo, Beograd, i dr.
T2  - Archives of Biological Sciences
T1  - Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia
EP  - 246
IS  - 2
SP  - 239
VL  - 69
DO  - 10.2298/ABS160325091L
ER  - 

@article{
author = "Lazić, Jelena and Kotur, Nikola and Krstovski, Nada and Dokmanović, Lidija and Zukić, Branka and Predojević-Samardzić, Jelica and Zivotić, Maja and Milosević, Goran and Dorić, Milica and Janić, Dragana and Pavlović, Sonja",
year = "2017",
abstract = "Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C gt T and MTHFR c.1298A gt C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A gt C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C gt T nor MTHFR c.1298A gt C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.",
publisher = "Srpsko biološko društvo, Beograd, i dr.",
journal = "Archives of Biological Sciences",
title = "Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia",
pages = "246-239",
number = "2",
volume = "69",
doi = "10.2298/ABS160325091L"
}

Lazić, J., Kotur, N., Krstovski, N., Dokmanović, L., Zukić, B., Predojević-Samardzić, J., Zivotić, M., Milosević, G., Dorić, M., Janić, D.,& Pavlović, S.. (2017). Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. in Archives of Biological Sciences
Srpsko biološko društvo, Beograd, i dr.., 69(2), 239-246.
https://doi.org/10.2298/ABS160325091L

Lazić J, Kotur N, Krstovski N, Dokmanović L, Zukić B, Predojević-Samardzić J, Zivotić M, Milosević G, Dorić M, Janić D, Pavlović S. Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. in Archives of Biological Sciences. 2017;69(2):239-246.
doi:10.2298/ABS160325091L .

Lazić, Jelena, Kotur, Nikola, Krstovski, Nada, Dokmanović, Lidija, Zukić, Branka, Predojević-Samardzić, Jelica, Zivotić, Maja, Milosević, Goran, Dorić, Milica, Janić, Dragana, Pavlović, Sonja, "Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia" in Archives of Biological Sciences, 69, no. 2 (2017):239-246,
https://doi.org/10.2298/ABS160325091L . .

TY  - JOUR
AU  - Janković, Srdja
AU  - Marjanović, Irena
AU  - Tošić, Nataša
AU  - Kotur, Nikola
AU  - Dokmanović, Lidija
AU  - Skorić, Dejan
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Rodić, Predrag
AU  - Pavlović, Sonja
AU  - Janić, Dragana
PY  - 2016
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/946
AB  - Acute leukemias constitute the most common malignancy in childhood, accounting for 25-35% of all cancer in children. They are divided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Genetic susceptibility is known to play a major role in childhood leukemias. Wilms tumor (WT)1 is a zinc finger transcription factor involved in regulating the process of cell differentiation; it has been implicated in a wide range of human neoplasms. WT1 overexpression in the bone marrow at diagnosis is reported to be an independent negative prognostic factor in adults and children with AML. The aim of the present investigation was to determine the expression of WT1 in the bone marrow of children with AML and ALL in Serbia and its possible impact on patient survival. We determined bone marrow WT1 expression levels by reverse -transcription polymerase chain reaction (RT-PCR) at diagnosis in 20 children with AML and 20 children with ALL (16 B-ALL and 4 T-ALL), as well as 15 age- and sex-matched controls who were evaluated for immune thrombocytopenic purpura (ITP). For children with AML, follow-up samples were also analyzed one month after treatment initiation and at variable later timepoints of control punctures. The results were normalized based on WT1 expression in controls. We found that children with AML had significantly higher WT1 expression at diagnosis (median SD: 139.42 244.03) than those with ALL (1.18 54.37; Mann -Whitney U=82; p lt 0.01) and ITP (0.76 1.01; U=32; p lt 0.01). Patients with T-ALL had higher WT1 expression than those with B-ALL, though significance was not reached due to subgroup size; differences between AML subgroups according to the French-American-British (FAB) classification were also below the level of significance, though a tendency toward higher values in M3 and M4 leukemias was notable. There was also a tendency toward higher values in 14 children with AML who were still alive after a median follow-up of 1.5 years (181.42 192.52) than in 6 who succumbed to the disease (104.29 354.87). All children with AML who had WT1 expression 1 month after diagnosis below the fourth quartile (10 of 10) were still alive, while only 2 of 5 with 1 -month WT1 expression in the fourth quartile survived (Fisher's exact test: p=0.0952). Taken together, our results support a role for WT1 in the diagnostic workup in children with acute leukemia, although it needs to be considered in view of a complex and indvidualized context.
PB  - Društvo genetičara Srbije, Beograd
T2  - Genetika-Belgrade
T1  - Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia
EP  - 421
IS  - 1
SP  - 409
VL  - 48
DO  - 10.2298/GENSR1601409J
ER  - 

@article{
author = "Janković, Srdja and Marjanović, Irena and Tošić, Nataša and Kotur, Nikola and Dokmanović, Lidija and Skorić, Dejan and Krstovski, Nada and Lazić, Jelena and Rodić, Predrag and Pavlović, Sonja and Janić, Dragana",
year = "2016",
abstract = "Acute leukemias constitute the most common malignancy in childhood, accounting for 25-35% of all cancer in children. They are divided into acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Genetic susceptibility is known to play a major role in childhood leukemias. Wilms tumor (WT)1 is a zinc finger transcription factor involved in regulating the process of cell differentiation; it has been implicated in a wide range of human neoplasms. WT1 overexpression in the bone marrow at diagnosis is reported to be an independent negative prognostic factor in adults and children with AML. The aim of the present investigation was to determine the expression of WT1 in the bone marrow of children with AML and ALL in Serbia and its possible impact on patient survival. We determined bone marrow WT1 expression levels by reverse -transcription polymerase chain reaction (RT-PCR) at diagnosis in 20 children with AML and 20 children with ALL (16 B-ALL and 4 T-ALL), as well as 15 age- and sex-matched controls who were evaluated for immune thrombocytopenic purpura (ITP). For children with AML, follow-up samples were also analyzed one month after treatment initiation and at variable later timepoints of control punctures. The results were normalized based on WT1 expression in controls. We found that children with AML had significantly higher WT1 expression at diagnosis (median SD: 139.42 244.03) than those with ALL (1.18 54.37; Mann -Whitney U=82; p lt 0.01) and ITP (0.76 1.01; U=32; p lt 0.01). Patients with T-ALL had higher WT1 expression than those with B-ALL, though significance was not reached due to subgroup size; differences between AML subgroups according to the French-American-British (FAB) classification were also below the level of significance, though a tendency toward higher values in M3 and M4 leukemias was notable. There was also a tendency toward higher values in 14 children with AML who were still alive after a median follow-up of 1.5 years (181.42 192.52) than in 6 who succumbed to the disease (104.29 354.87). All children with AML who had WT1 expression 1 month after diagnosis below the fourth quartile (10 of 10) were still alive, while only 2 of 5 with 1 -month WT1 expression in the fourth quartile survived (Fisher's exact test: p=0.0952). Taken together, our results support a role for WT1 in the diagnostic workup in children with acute leukemia, although it needs to be considered in view of a complex and indvidualized context.",
publisher = "Društvo genetičara Srbije, Beograd",
journal = "Genetika-Belgrade",
title = "Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia",
pages = "421-409",
number = "1",
volume = "48",
doi = "10.2298/GENSR1601409J"
}

Janković, S., Marjanović, I., Tošić, N., Kotur, N., Dokmanović, L., Skorić, D., Krstovski, N., Lazić, J., Rodić, P., Pavlović, S.,& Janić, D.. (2016). Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia. in Genetika-Belgrade
Društvo genetičara Srbije, Beograd., 48(1), 409-421.
https://doi.org/10.2298/GENSR1601409J

Janković S, Marjanović I, Tošić N, Kotur N, Dokmanović L, Skorić D, Krstovski N, Lazić J, Rodić P, Pavlović S, Janić D. Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia. in Genetika-Belgrade. 2016;48(1):409-421.
doi:10.2298/GENSR1601409J .

Janković, Srdja, Marjanović, Irena, Tošić, Nataša, Kotur, Nikola, Dokmanović, Lidija, Skorić, Dejan, Krstovski, Nada, Lazić, Jelena, Rodić, Predrag, Pavlović, Sonja, Janić, Dragana, "Wilms tumor (wt)1 gene expression in children with acute leukemia in Serbia" in Genetika-Belgrade, 48, no. 1 (2016):409-421,
https://doi.org/10.2298/GENSR1601409J . .

TY  - JOUR
AU  - Ugrin, Milena
AU  - Stojiljković, Maja
AU  - Zukić, Branka
AU  - Klaassen, Kristel
AU  - Katsila, Theodora
AU  - Komazec, Jovana
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Patrinos, George P.
AU  - Pavlović, Sonja
PY  - 2016
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/975
AB  - Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by persistent -globin gene expression and synthesis of high levels of fetal hemoglobin (Hb F; 22) during adult life. It is usually caused by promoter variants or large deletions affecting the human fetal globin (HBG1 and HBG2) genes. Some of these HPFH-causing variants, such as HBG2: g.-158C gt T, exert their effect only under conditions of erythropoietic stress, typical for -thalassemia (-thal) patients. Namely, the presence of HBG2: g.-158C gt T favors a higher Hb F response, while it has little effect in healthy individuals. We analyzed a previously reported deletion residing in the promoter region of the HBG1 gene (HBG1: g.-225_-222delAGCA), both in normal conditions and under conditions of erythropoietic stress. Our results indicate that this deletion is responsible for decreased HBG1 gene expression. Specifically, this deletion was shown to result in drastically reduced reporter gene expression in K562 cells, compared to the wild-type sequence but only under conditions of erythropoietic stress, mimicked by introduction of erythropoietin (EPO) into the cell culture. Also, electrophoretic mobility shift analysis showed that the HBG1: g.-225_-222delAGCA deletion creates additional transcriptional factors' binding sites, which, we propose, bind a transcriptional repressor, thus decreasing the HBG1 gene promoter activity. These results are consistent with in silico analysis, which indicated that this deletion creates a binding site for GATA1, known to be a repressor of the -globin gene expression. These data confirm the regulatory role of the HBG1: g.-225_-222 region that exerts its effect under conditions of erythropoietic stress characteristic for -thal patients.
PB  - Taylor & Francis Ltd, Abingdon
T2  - Hemoglobin
T1  - Functional Analysis of an (A)gamma-Globin Gene Promoter Variant (HBG1: g.-225_-222delAGCA) Underlines Its Role in Increasing Fetal Hemoglobin Levels Under Erythropoietic Stress
EP  - 52
IS  - 1
SP  - 48
VL  - 40
DO  - 10.3109/03630269.2015.1107842
ER  - 

@article{
author = "Ugrin, Milena and Stojiljković, Maja and Zukić, Branka and Klaassen, Kristel and Katsila, Theodora and Komazec, Jovana and Dokmanović, Lidija and Janić, Dragana and Patrinos, George P. and Pavlović, Sonja",
year = "2016",
abstract = "Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by persistent -globin gene expression and synthesis of high levels of fetal hemoglobin (Hb F; 22) during adult life. It is usually caused by promoter variants or large deletions affecting the human fetal globin (HBG1 and HBG2) genes. Some of these HPFH-causing variants, such as HBG2: g.-158C gt T, exert their effect only under conditions of erythropoietic stress, typical for -thalassemia (-thal) patients. Namely, the presence of HBG2: g.-158C gt T favors a higher Hb F response, while it has little effect in healthy individuals. We analyzed a previously reported deletion residing in the promoter region of the HBG1 gene (HBG1: g.-225_-222delAGCA), both in normal conditions and under conditions of erythropoietic stress. Our results indicate that this deletion is responsible for decreased HBG1 gene expression. Specifically, this deletion was shown to result in drastically reduced reporter gene expression in K562 cells, compared to the wild-type sequence but only under conditions of erythropoietic stress, mimicked by introduction of erythropoietin (EPO) into the cell culture. Also, electrophoretic mobility shift analysis showed that the HBG1: g.-225_-222delAGCA deletion creates additional transcriptional factors' binding sites, which, we propose, bind a transcriptional repressor, thus decreasing the HBG1 gene promoter activity. These results are consistent with in silico analysis, which indicated that this deletion creates a binding site for GATA1, known to be a repressor of the -globin gene expression. These data confirm the regulatory role of the HBG1: g.-225_-222 region that exerts its effect under conditions of erythropoietic stress characteristic for -thal patients.",
publisher = "Taylor & Francis Ltd, Abingdon",
journal = "Hemoglobin",
title = "Functional Analysis of an (A)gamma-Globin Gene Promoter Variant (HBG1: g.-225_-222delAGCA) Underlines Its Role in Increasing Fetal Hemoglobin Levels Under Erythropoietic Stress",
pages = "52-48",
number = "1",
volume = "40",
doi = "10.3109/03630269.2015.1107842"
}

Ugrin, M., Stojiljković, M., Zukić, B., Klaassen, K., Katsila, T., Komazec, J., Dokmanović, L., Janić, D., Patrinos, G. P.,& Pavlović, S.. (2016). Functional Analysis of an (A)gamma-Globin Gene Promoter Variant (HBG1: g.-225_-222delAGCA) Underlines Its Role in Increasing Fetal Hemoglobin Levels Under Erythropoietic Stress. in Hemoglobin
Taylor & Francis Ltd, Abingdon., 40(1), 48-52.
https://doi.org/10.3109/03630269.2015.1107842

Ugrin M, Stojiljković M, Zukić B, Klaassen K, Katsila T, Komazec J, Dokmanović L, Janić D, Patrinos GP, Pavlović S. Functional Analysis of an (A)gamma-Globin Gene Promoter Variant (HBG1: g.-225_-222delAGCA) Underlines Its Role in Increasing Fetal Hemoglobin Levels Under Erythropoietic Stress. in Hemoglobin. 2016;40(1):48-52.
doi:10.3109/03630269.2015.1107842 .

Ugrin, Milena, Stojiljković, Maja, Zukić, Branka, Klaassen, Kristel, Katsila, Theodora, Komazec, Jovana, Dokmanović, Lidija, Janić, Dragana, Patrinos, George P., Pavlović, Sonja, "Functional Analysis of an (A)gamma-Globin Gene Promoter Variant (HBG1: g.-225_-222delAGCA) Underlines Its Role in Increasing Fetal Hemoglobin Levels Under Erythropoietic Stress" in Hemoglobin, 40, no. 1 (2016):48-52,
https://doi.org/10.3109/03630269.2015.1107842 . .

TY  - JOUR
AU  - Marjanović, Irena
AU  - Perić, Jelena
AU  - Stanić, Bojana
AU  - Pejanović, Nadja
AU  - Lucić, Bojana
AU  - Karan-Đurašević, Teodora
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Janković, Srdja
AU  - Suvajdžić-Vuković, Nada
AU  - Tomin, Dragica
AU  - Perisić, Ognjen
AU  - Rakocević, Goran
AU  - Popović, Milos
AU  - Pavlović, Sonja
AU  - Tošić, Nataša
PY  - 2016
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/932
AB  - The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 x per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.
PB  - Sage Publications Ltd, London
T2  - Tumor Biology
T1  - Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease
EP  - 13401
IS  - 10
SP  - 13391
VL  - 37
DO  - 10.1007/s13277-016-5142-7
ER  - 

@article{
author = "Marjanović, Irena and Perić, Jelena and Stanić, Bojana and Pejanović, Nadja and Lucić, Bojana and Karan-Đurašević, Teodora and Janić, Dragana and Dokmanović, Lidija and Janković, Srdja and Suvajdžić-Vuković, Nada and Tomin, Dragica and Perisić, Ognjen and Rakocević, Goran and Popović, Milos and Pavlović, Sonja and Tošić, Nataša",
year = "2016",
abstract = "The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 x per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.",
publisher = "Sage Publications Ltd, London",
journal = "Tumor Biology",
title = "Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease",
pages = "13401-13391",
number = "10",
volume = "37",
doi = "10.1007/s13277-016-5142-7"
}

Marjanović, I., Perić, J., Stanić, B., Pejanović, N., Lucić, B., Karan-Đurašević, T., Janić, D., Dokmanović, L., Janković, S., Suvajdžić-Vuković, N., Tomin, D., Perisić, O., Rakocević, G., Popović, M., Pavlović, S.,& Tošić, N.. (2016). Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease. in Tumor Biology
Sage Publications Ltd, London., 37(10), 13391-13401.
https://doi.org/10.1007/s13277-016-5142-7

Marjanović I, Perić J, Stanić B, Pejanović N, Lucić B, Karan-Đurašević T, Janić D, Dokmanović L, Janković S, Suvajdžić-Vuković N, Tomin D, Perisić O, Rakocević G, Popović M, Pavlović S, Tošić N. Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease. in Tumor Biology. 2016;37(10):13391-13401.
doi:10.1007/s13277-016-5142-7 .

Marjanović, Irena, Perić, Jelena, Stanić, Bojana, Pejanović, Nadja, Lucić, Bojana, Karan-Đurašević, Teodora, Janić, Dragana, Dokmanović, Lidija, Janković, Srdja, Suvajdžić-Vuković, Nada, Tomin, Dragica, Perisić, Ognjen, Rakocević, Goran, Popović, Milos, Pavlović, Sonja, Tošić, Nataša, "Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease" in Tumor Biology, 37, no. 10 (2016):13391-13401,
https://doi.org/10.1007/s13277-016-5142-7 . .

TY  - JOUR
AU  - Kotur, Nikola
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Stanković, Biljana
AU  - Krstovski, Nada
AU  - Tošić, Nataša
AU  - Katsila, Theodora
AU  - Patrinos, George P.
AU  - Zukić, Branka
AU  - Pavlović, Sonja
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/842
AB  - Aims: 6-mercaptopurine influences in vitro TPMT gene expression in a TPMT promoter variable number of tandem repeats (VNTR)-dependent manner. We studied TPMT expression following 6-mercaptopurine and methotrexate administration in childhood acute lymphoblastic leukemia (ALL) patients and the pharmacogenomic potential of the VNTR architecture. Materials & methods:TPMT gene expression was determined in childhood ALL patients at diagnosis (n = 57) and during the maintenance therapy (n = 27). Results: A threefold increase of TPMT gene expression was obtained during maintenance therapy, modulated by the architecture of the VNTR region. Conclusion: The TPMT promoter genetic variants need to be considered at the very beginning of the maintenance therapy for childhood ALL patients. The TPMT promoter VNTR region may serve as a pharmacogenomic biomarker when introducing thiopurine therapy.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner
EP  - 1712
IS  - 15
SP  - 1701
VL  - 16
DO  - 10.2217/pgs.15.109
ER  - 

@article{
author = "Kotur, Nikola and Dokmanović, Lidija and Janić, Dragana and Stanković, Biljana and Krstovski, Nada and Tošić, Nataša and Katsila, Theodora and Patrinos, George P. and Zukić, Branka and Pavlović, Sonja",
year = "2015",
abstract = "Aims: 6-mercaptopurine influences in vitro TPMT gene expression in a TPMT promoter variable number of tandem repeats (VNTR)-dependent manner. We studied TPMT expression following 6-mercaptopurine and methotrexate administration in childhood acute lymphoblastic leukemia (ALL) patients and the pharmacogenomic potential of the VNTR architecture. Materials & methods:TPMT gene expression was determined in childhood ALL patients at diagnosis (n = 57) and during the maintenance therapy (n = 27). Results: A threefold increase of TPMT gene expression was obtained during maintenance therapy, modulated by the architecture of the VNTR region. Conclusion: The TPMT promoter genetic variants need to be considered at the very beginning of the maintenance therapy for childhood ALL patients. The TPMT promoter VNTR region may serve as a pharmacogenomic biomarker when introducing thiopurine therapy.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner",
pages = "1712-1701",
number = "15",
volume = "16",
doi = "10.2217/pgs.15.109"
}

Kotur, N., Dokmanović, L., Janić, D., Stanković, B., Krstovski, N., Tošić, N., Katsila, T., Patrinos, G. P., Zukić, B.,& Pavlović, S.. (2015). TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner. in Pharmacogenomics
Future Medicine Ltd, London., 16(15), 1701-1712.
https://doi.org/10.2217/pgs.15.109

Kotur N, Dokmanović L, Janić D, Stanković B, Krstovski N, Tošić N, Katsila T, Patrinos GP, Zukić B, Pavlović S. TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner. in Pharmacogenomics. 2015;16(15):1701-1712.
doi:10.2217/pgs.15.109 .

Kotur, Nikola, Dokmanović, Lidija, Janić, Dragana, Stanković, Biljana, Krstovski, Nada, Tošić, Nataša, Katsila, Theodora, Patrinos, George P., Zukić, Branka, Pavlović, Sonja, "TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner" in Pharmacogenomics, 16, no. 15 (2015):1701-1712,
https://doi.org/10.2217/pgs.15.109 . .

TY  - JOUR
AU  - Rodić, Predrag
AU  - Pavlović, Sonja
AU  - Kostić, Tatjana
AU  - Suvajdžić-Vuković, Nada
AU  - Đorđević, Maja
AU  - Sumarac, Zorica
AU  - Dajak, Marijana
AU  - Bonaci-Nikolić, Branka
AU  - Janić, Dragana
PY  - 2013
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/621
AB  - Introduction: We evaluated a novel approach for investigation of lymphocyte dysregulation in Gaucher patients by including determination of IgH and TCR gene rearrangements together with levels of immunoglobulins, natural autoantibodies as well as presence of monoclonal protein. Materials and methods: Measurement of serum immunoglobulins, monoclonal immunoglobulins, selected autoantibodies, as well as analysis of immunoglobulin heavy chain and T cell receptor gene rearrangements. Results: Immunoglobulin disorder was detected in 29.6% patients, 40.7% demonstrated presence of B cell clonality and 44.4% demonstrated presence of autoantibodies. In five patients in our series, the presence of IgH gene rearrangement was the only detectable indicator of B cell dysfunction. TCR gene rearrangements were not found in any of the patients. Conclusion: Based on our results, we propose IgH gene rearrangements as a new biomarker for investigation of B cell dysfunction occurring as a complication of Gaucher disease.
PB  - Academic Press Inc Elsevier Science, San Diego
T2  - Blood Cells Molecules and Diseases
T1  - Gammopathy and B lymphocyte clonality in patients with Gaucher type I disease
EP  - 225
IS  - 3
SP  - 222
VL  - 50
DO  - 10.1016/j.bcmd.2012.11.012
ER  - 

@article{
author = "Rodić, Predrag and Pavlović, Sonja and Kostić, Tatjana and Suvajdžić-Vuković, Nada and Đorđević, Maja and Sumarac, Zorica and Dajak, Marijana and Bonaci-Nikolić, Branka and Janić, Dragana",
year = "2013",
abstract = "Introduction: We evaluated a novel approach for investigation of lymphocyte dysregulation in Gaucher patients by including determination of IgH and TCR gene rearrangements together with levels of immunoglobulins, natural autoantibodies as well as presence of monoclonal protein. Materials and methods: Measurement of serum immunoglobulins, monoclonal immunoglobulins, selected autoantibodies, as well as analysis of immunoglobulin heavy chain and T cell receptor gene rearrangements. Results: Immunoglobulin disorder was detected in 29.6% patients, 40.7% demonstrated presence of B cell clonality and 44.4% demonstrated presence of autoantibodies. In five patients in our series, the presence of IgH gene rearrangement was the only detectable indicator of B cell dysfunction. TCR gene rearrangements were not found in any of the patients. Conclusion: Based on our results, we propose IgH gene rearrangements as a new biomarker for investigation of B cell dysfunction occurring as a complication of Gaucher disease.",
publisher = "Academic Press Inc Elsevier Science, San Diego",
journal = "Blood Cells Molecules and Diseases",
title = "Gammopathy and B lymphocyte clonality in patients with Gaucher type I disease",
pages = "225-222",
number = "3",
volume = "50",
doi = "10.1016/j.bcmd.2012.11.012"
}

Rodić, P., Pavlović, S., Kostić, T., Suvajdžić-Vuković, N., Đorđević, M., Sumarac, Z., Dajak, M., Bonaci-Nikolić, B.,& Janić, D.. (2013). Gammopathy and B lymphocyte clonality in patients with Gaucher type I disease. in Blood Cells Molecules and Diseases
Academic Press Inc Elsevier Science, San Diego., 50(3), 222-225.
https://doi.org/10.1016/j.bcmd.2012.11.012

Rodić P, Pavlović S, Kostić T, Suvajdžić-Vuković N, Đorđević M, Sumarac Z, Dajak M, Bonaci-Nikolić B, Janić D. Gammopathy and B lymphocyte clonality in patients with Gaucher type I disease. in Blood Cells Molecules and Diseases. 2013;50(3):222-225.
doi:10.1016/j.bcmd.2012.11.012 .

Rodić, Predrag, Pavlović, Sonja, Kostić, Tatjana, Suvajdžić-Vuković, Nada, Đorđević, Maja, Sumarac, Zorica, Dajak, Marijana, Bonaci-Nikolić, Branka, Janić, Dragana, "Gammopathy and B lymphocyte clonality in patients with Gaucher type I disease" in Blood Cells Molecules and Diseases, 50, no. 3 (2013):222-225,
https://doi.org/10.1016/j.bcmd.2012.11.012 . .

TY  - JOUR
AU  - Kotur, Nikola
AU  - Stanković, Biljana
AU  - Klaassen, Kristel
AU  - Georgitsi, Marianthi
AU  - Vicha, Anna
AU  - Leontari, Iliana
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Krstovski, Nada
AU  - Karan-Đurašević, Teodora
AU  - Ugrin, Milena
AU  - Stojiljković, Maja
AU  - Nikčević, Gordana
AU  - Simeonidis, Argiris
AU  - Sivolapenko, Gregory
AU  - Pavlović, Sonja
AU  - Partinos, George P.
AU  - Zukić, Branka
PY  - 2012
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/554
AB  - Aim: TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an A(n)B(m)C architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription. Materials, methods & results: Here we demonstrate, using reporter assays, that 6-mercaptopurine (6-MP) treatment results in a VNTR architecture-dependent decrease of TPMT gene transcription, mediated by the binding of newly recruited protein complexes to the TPMT gene promoter, upon 6-MP treatment. We also show that acute lymphoblastic leukemia patients undergoing 6-MP treatment display a VNTR architecture-dependent response to 6-MP. Conclusion: These data suggest that the TPMT gene promoter VNTR architecture can be potentially used as a pharmacogenomic marker to predict toxicity due to 6-MP treatment in acute lymphoblastic leukemia patients.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - 6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner
EP  - 295
IS  - 3
SP  - 283
VL  - 13
DO  - 10.2217/PGS.11.153
ER  - 

@article{
author = "Kotur, Nikola and Stanković, Biljana and Klaassen, Kristel and Georgitsi, Marianthi and Vicha, Anna and Leontari, Iliana and Dokmanović, Lidija and Janić, Dragana and Krstovski, Nada and Karan-Đurašević, Teodora and Ugrin, Milena and Stojiljković, Maja and Nikčević, Gordana and Simeonidis, Argiris and Sivolapenko, Gregory and Pavlović, Sonja and Partinos, George P. and Zukić, Branka",
year = "2012",
abstract = "Aim: TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an A(n)B(m)C architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription. Materials, methods & results: Here we demonstrate, using reporter assays, that 6-mercaptopurine (6-MP) treatment results in a VNTR architecture-dependent decrease of TPMT gene transcription, mediated by the binding of newly recruited protein complexes to the TPMT gene promoter, upon 6-MP treatment. We also show that acute lymphoblastic leukemia patients undergoing 6-MP treatment display a VNTR architecture-dependent response to 6-MP. Conclusion: These data suggest that the TPMT gene promoter VNTR architecture can be potentially used as a pharmacogenomic marker to predict toxicity due to 6-MP treatment in acute lymphoblastic leukemia patients.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner",
pages = "295-283",
number = "3",
volume = "13",
doi = "10.2217/PGS.11.153"
}

Kotur, N., Stanković, B., Klaassen, K., Georgitsi, M., Vicha, A., Leontari, I., Dokmanović, L., Janić, D., Krstovski, N., Karan-Đurašević, T., Ugrin, M., Stojiljković, M., Nikčević, G., Simeonidis, A., Sivolapenko, G., Pavlović, S., Partinos, G. P.,& Zukić, B.. (2012). 6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner. in Pharmacogenomics
Future Medicine Ltd, London., 13(3), 283-295.
https://doi.org/10.2217/PGS.11.153

Kotur N, Stanković B, Klaassen K, Georgitsi M, Vicha A, Leontari I, Dokmanović L, Janić D, Krstovski N, Karan-Đurašević T, Ugrin M, Stojiljković M, Nikčević G, Simeonidis A, Sivolapenko G, Pavlović S, Partinos GP, Zukić B. 6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner. in Pharmacogenomics. 2012;13(3):283-295.
doi:10.2217/PGS.11.153 .

Kotur, Nikola, Stanković, Biljana, Klaassen, Kristel, Georgitsi, Marianthi, Vicha, Anna, Leontari, Iliana, Dokmanović, Lidija, Janić, Dragana, Krstovski, Nada, Karan-Đurašević, Teodora, Ugrin, Milena, Stojiljković, Maja, Nikčević, Gordana, Simeonidis, Argiris, Sivolapenko, Gregory, Pavlović, Sonja, Partinos, George P., Zukić, Branka, "6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner" in Pharmacogenomics, 13, no. 3 (2012):283-295,
https://doi.org/10.2217/PGS.11.153 . .

TY  - JOUR
AU  - Zukić, Branka
AU  - Radmilović Milena
AU  - Stojiljković, Maja
AU  - Tošić, Nataša
AU  - Pourfarzad, Farzin
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Čolović, Nataša
AU  - Philipsen, Sjaak
AU  - Patrinos, George P.
AU  - Pavlović, Sonja
PY  - 2010
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/422
AB  - Aims: Thiopurine S-methyltransferase (TPMT) activity is polymorphic, and a trimodal distribution has been demonstrated in Caucasians (low, intermediate and high methylator groups). The TPMT gene promoter contains a variable number of three GC-rich tandem repeats, namely A, B and C, ranging from three to nine in length in a A(n)B(m),C architecture. Materials & methods: Here, we investigated the influence of number and type of TPMT gene promoter tandem repeats on human TPMT gene transcription in K562 cells transiently transfected with reporter constructs bearing various variable number of tandem repeats (VNTR) and addressed the interaction of transcription factor binding to the VNTRs by electrophoretic mobility shift assays. Results: We found that the distribution patterns of VNTR alleles do not significantly differ among acute lymphoblastic leukemia patients, acute myeloid leukemia patients and normal individuals. We also demonstrated that the A repeat has a negative effect in TPMT gene transcription and that a positive regulatory element, identified immediately upstream to the VNTR region of the TPMT gene promoter, is indispensable for TPMT gene transcription. Our electrophoretic mobility shift assay analysis indicated that the Sp1 and Sp3 transcription factors bind to the VNTR repeats. Conclusion: Overall, our data underline that both the number and type of VNTRs, as well as the upstream regulatory region of the TPMT gene promoter, determine the overall level of TPMT gene transcription. It remains to be seen whether these VNTRs can be employed as pharmacogenetic markers to individualize thiopurine therapy.
PB  - Future Medicine Ltd, London
T2  - Pharmacogenomics
T1  - Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription
EP  - 557
IS  - 4
SP  - 547
VL  - 11
DO  - 10.2217/PGS.10.7
ER  - 

@article{
author = "Zukić, Branka and Radmilović Milena and Stojiljković, Maja and Tošić, Nataša and Pourfarzad, Farzin and Dokmanović, Lidija and Janić, Dragana and Čolović, Nataša and Philipsen, Sjaak and Patrinos, George P. and Pavlović, Sonja",
year = "2010",
abstract = "Aims: Thiopurine S-methyltransferase (TPMT) activity is polymorphic, and a trimodal distribution has been demonstrated in Caucasians (low, intermediate and high methylator groups). The TPMT gene promoter contains a variable number of three GC-rich tandem repeats, namely A, B and C, ranging from three to nine in length in a A(n)B(m),C architecture. Materials & methods: Here, we investigated the influence of number and type of TPMT gene promoter tandem repeats on human TPMT gene transcription in K562 cells transiently transfected with reporter constructs bearing various variable number of tandem repeats (VNTR) and addressed the interaction of transcription factor binding to the VNTRs by electrophoretic mobility shift assays. Results: We found that the distribution patterns of VNTR alleles do not significantly differ among acute lymphoblastic leukemia patients, acute myeloid leukemia patients and normal individuals. We also demonstrated that the A repeat has a negative effect in TPMT gene transcription and that a positive regulatory element, identified immediately upstream to the VNTR region of the TPMT gene promoter, is indispensable for TPMT gene transcription. Our electrophoretic mobility shift assay analysis indicated that the Sp1 and Sp3 transcription factors bind to the VNTR repeats. Conclusion: Overall, our data underline that both the number and type of VNTRs, as well as the upstream regulatory region of the TPMT gene promoter, determine the overall level of TPMT gene transcription. It remains to be seen whether these VNTRs can be employed as pharmacogenetic markers to individualize thiopurine therapy.",
publisher = "Future Medicine Ltd, London",
journal = "Pharmacogenomics",
title = "Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription",
pages = "557-547",
number = "4",
volume = "11",
doi = "10.2217/PGS.10.7"
}

Zukić, B., Radmilović Milena, Stojiljković, M., Tošić, N., Pourfarzad, F., Dokmanović, L., Janić, D., Čolović, N., Philipsen, S., Patrinos, G. P.,& Pavlović, S.. (2010). Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription. in Pharmacogenomics
Future Medicine Ltd, London., 11(4), 547-557.
https://doi.org/10.2217/PGS.10.7

Zukić B, Radmilović Milena, Stojiljković M, Tošić N, Pourfarzad F, Dokmanović L, Janić D, Čolović N, Philipsen S, Patrinos GP, Pavlović S. Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription. in Pharmacogenomics. 2010;11(4):547-557.
doi:10.2217/PGS.10.7 .

Zukić, Branka, Radmilović Milena, Stojiljković, Maja, Tošić, Nataša, Pourfarzad, Farzin, Dokmanović, Lidija, Janić, Dragana, Čolović, Nataša, Philipsen, Sjaak, Patrinos, George P., Pavlović, Sonja, "Functional analysis of the role of the TPMT gene promoter VNTR polymorphism in TPMT gene transcription" in Pharmacogenomics, 11, no. 4 (2010):547-557,
https://doi.org/10.2217/PGS.10.7 . .

TY  - JOUR
AU  - Radmilović Milena
AU  - Zukić, Branka
AU  - Stanković, Biljana
AU  - Karan-Đurašević, Teodora
AU  - Stojiljković, Maja
AU  - Spasovski, Vesna
AU  - Tošić, Nataša
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Pavlović, Sonja
PY  - 2010
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/401
AB  - Thalassemia syndromes constitute a group of genetic disorders, widespread throughout the world. The present study contains data on thalassemia syndromes and their chromosomal environment obtained in Serbia over a period of 10 years. Ten different beta-thalassemia (beta-thal) mutations and two hemoglobin (Hb) variants were detected in 127 members of 68 families. Hb Lepore-Boston-Washington (Lepore-BW) (delta 87Gln-beta-IVS-II-8), a thalassemic Hb variant, was shown to be the most common cause of thalassemia in Serbia. Haplotype analyses of the beta-globin gene clusters of healthy individuals as well as of individuals affected with beta-thal showed that haplotype I was the most frequent haplotype in the Serbian population, followed by haplotypes II and IX. Two novel haplotypes were detected. Haplotype analyses showed the association between certain haplotypes and the most common thalassemic mutations. Results presented in this paper will update the Serbian national mutation database and contribute to a better understanding of genographic history of South European and Balkan populations.
PB  - Taylor & Francis Ltd, Abingdon
T2  - Hemoglobin
T1  - Thalassemia syndromes in Serbia: an update
EP  - 485
IS  - 5
SP  - 477
VL  - 34
DO  - 10.3109/03630269.2010.513637
ER  - 

@article{
author = "Radmilović Milena and Zukić, Branka and Stanković, Biljana and Karan-Đurašević, Teodora and Stojiljković, Maja and Spasovski, Vesna and Tošić, Nataša and Dokmanović, Lidija and Janić, Dragana and Pavlović, Sonja",
year = "2010",
abstract = "Thalassemia syndromes constitute a group of genetic disorders, widespread throughout the world. The present study contains data on thalassemia syndromes and their chromosomal environment obtained in Serbia over a period of 10 years. Ten different beta-thalassemia (beta-thal) mutations and two hemoglobin (Hb) variants were detected in 127 members of 68 families. Hb Lepore-Boston-Washington (Lepore-BW) (delta 87Gln-beta-IVS-II-8), a thalassemic Hb variant, was shown to be the most common cause of thalassemia in Serbia. Haplotype analyses of the beta-globin gene clusters of healthy individuals as well as of individuals affected with beta-thal showed that haplotype I was the most frequent haplotype in the Serbian population, followed by haplotypes II and IX. Two novel haplotypes were detected. Haplotype analyses showed the association between certain haplotypes and the most common thalassemic mutations. Results presented in this paper will update the Serbian national mutation database and contribute to a better understanding of genographic history of South European and Balkan populations.",
publisher = "Taylor & Francis Ltd, Abingdon",
journal = "Hemoglobin",
title = "Thalassemia syndromes in Serbia: an update",
pages = "485-477",
number = "5",
volume = "34",
doi = "10.3109/03630269.2010.513637"
}

Radmilović Milena, Zukić, B., Stanković, B., Karan-Đurašević, T., Stojiljković, M., Spasovski, V., Tošić, N., Dokmanović, L., Janić, D.,& Pavlović, S.. (2010). Thalassemia syndromes in Serbia: an update. in Hemoglobin
Taylor & Francis Ltd, Abingdon., 34(5), 477-485.
https://doi.org/10.3109/03630269.2010.513637

Radmilović Milena, Zukić B, Stanković B, Karan-Đurašević T, Stojiljković M, Spasovski V, Tošić N, Dokmanović L, Janić D, Pavlović S. Thalassemia syndromes in Serbia: an update. in Hemoglobin. 2010;34(5):477-485.
doi:10.3109/03630269.2010.513637 .

Radmilović Milena, Zukić, Branka, Stanković, Biljana, Karan-Đurašević, Teodora, Stojiljković, Maja, Spasovski, Vesna, Tošić, Nataša, Dokmanović, Lidija, Janić, Dragana, Pavlović, Sonja, "Thalassemia syndromes in Serbia: an update" in Hemoglobin, 34, no. 5 (2010):477-485,
https://doi.org/10.3109/03630269.2010.513637 . .

TY  - JOUR
AU  - Krstovski, Nada
AU  - Tošić, Nataša
AU  - Janić, Dragana
AU  - Dokmanović, Lidija
AU  - Kuzmanović, Milos
AU  - Spasovski, Vesna
AU  - Pavlović, Sonja
PY  - 2010
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/446
AB  - Mutations in the fms-like tyrosine kinase 3 (FLT3) gene (internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain, FLT3/D835) as well as the nucleophosmin (NPM1) gene are the most common abnormalities in adult acute myeloid leukemia (AML). Their significance in pediatric AML is still unclear. In this study we evaluated the frequency of FLT3 and NPM1 mutations in childhood AML. We also examined clinical features and outcome of these patients. FLT3 and NPM1 mutations were analysed in 42 and 37 childhood AML patients, respectively, using polymerase chain reaction (PCR) and direct sequencing.FLT3 mutations were detected in 4/42 patients (9.5%). The frequencies of FLT3/ITD and FLT3/D835 were the same, 2/42 (4.7%). NMP1 mutations were found in 1/37 patients (2.7%). FLT3 gene mutations were correlated with induction failure. Here we report the results of the study of FLT3 and NPM1 gene mutations in childhood AML patients in Serbia. Low frequencies of these molecular markers point out that these abnormalities are rare in this cohort of patients. Comparative study of data on NPM1 mutations in childhood AML revealed that various NPM1 gene mutation types are associated with childhood AML. Our findings as well as previously reported data, contributes to a hypothesis of different biology and etiology of adult and childhood AML. More extensive studies of NPM1 and FLT3 mutations in childhood AML are needed to determine their biological and clinical importance.
PB  - Humana Press Inc, Totowa
T2  - Medical Oncology
T1  - Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature
EP  - 645
IS  - 3
SP  - 640
VL  - 27
DO  - 10.1007/s12032-009-9261-5
ER  - 

@article{
author = "Krstovski, Nada and Tošić, Nataša and Janić, Dragana and Dokmanović, Lidija and Kuzmanović, Milos and Spasovski, Vesna and Pavlović, Sonja",
year = "2010",
abstract = "Mutations in the fms-like tyrosine kinase 3 (FLT3) gene (internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain, FLT3/D835) as well as the nucleophosmin (NPM1) gene are the most common abnormalities in adult acute myeloid leukemia (AML). Their significance in pediatric AML is still unclear. In this study we evaluated the frequency of FLT3 and NPM1 mutations in childhood AML. We also examined clinical features and outcome of these patients. FLT3 and NPM1 mutations were analysed in 42 and 37 childhood AML patients, respectively, using polymerase chain reaction (PCR) and direct sequencing.FLT3 mutations were detected in 4/42 patients (9.5%). The frequencies of FLT3/ITD and FLT3/D835 were the same, 2/42 (4.7%). NMP1 mutations were found in 1/37 patients (2.7%). FLT3 gene mutations were correlated with induction failure. Here we report the results of the study of FLT3 and NPM1 gene mutations in childhood AML patients in Serbia. Low frequencies of these molecular markers point out that these abnormalities are rare in this cohort of patients. Comparative study of data on NPM1 mutations in childhood AML revealed that various NPM1 gene mutation types are associated with childhood AML. Our findings as well as previously reported data, contributes to a hypothesis of different biology and etiology of adult and childhood AML. More extensive studies of NPM1 and FLT3 mutations in childhood AML are needed to determine their biological and clinical importance.",
publisher = "Humana Press Inc, Totowa",
journal = "Medical Oncology",
title = "Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature",
pages = "645-640",
number = "3",
volume = "27",
doi = "10.1007/s12032-009-9261-5"
}

Krstovski, N., Tošić, N., Janić, D., Dokmanović, L., Kuzmanović, M., Spasovski, V.,& Pavlović, S.. (2010). Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature. in Medical Oncology
Humana Press Inc, Totowa., 27(3), 640-645.
https://doi.org/10.1007/s12032-009-9261-5

Krstovski N, Tošić N, Janić D, Dokmanović L, Kuzmanović M, Spasovski V, Pavlović S. Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature. in Medical Oncology. 2010;27(3):640-645.
doi:10.1007/s12032-009-9261-5 .

Krstovski, Nada, Tošić, Nataša, Janić, Dragana, Dokmanović, Lidija, Kuzmanović, Milos, Spasovski, Vesna, Pavlović, Sonja, "Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature" in Medical Oncology, 27, no. 3 (2010):640-645,
https://doi.org/10.1007/s12032-009-9261-5 . .

TY  - JOUR
AU  - Lazić, Jelena
AU  - Dokmanović, Lidija
AU  - Krstovski, Nada
AU  - Predojević, Jelica
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
AU  - Janić, Dragana
PY  - 2009
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/387
AB  - Uvod. Akutna limfoblastna leukemija (ALL) je maligna klonalna bolest i jedna od najčešćih neoplazmi dečjeg uzrasta. Primenom savremenih protokola postižu se visok stepen remisije i dugogodišnja stopa preživljavanja. Uvođenjem metoda molekularne genetike omogućeni su submikroskopska klasifikacija i praćenje minimalne rezidualne bolesti (MRB), odgovorne za nastanak recidiva. Cilj rada. Cilj rada je bilo ispitivanje učestalosti rearanžmana genskih lokusa za teške lance imunoglobulina (IgH) i T-ćelijski receptor (TCR) i njihova korelacija s kliničkim parametrima. Metode rada. Ispitano je 41 dete obolelo od ALL kojima je na dijagnozi rađena molekularna detekcija rearanžmana genskih lokusa za IgH i TCR metodom lančanog umnožavanja DNK (PCR). Posmatranje razvoja MRB je rađeno u indukcionoj fazi lečenja, kada se očekuje morfološki odgovor na terapiju. Rezultati. Rearanžman genskog lokusa za IgH zabeležen je kod 82,9%, a za TCR kod 56,1% ispitanika. Posle 33 dana indukcione terapije rearanžmani za IgH genski lokus su zabeleženi kod 39%, a za TCR kod 36,5% dece. Zaključak. Otkrivanje genetskih aberacija na molekularnom nivou i njihova korelacija sa standardnim prognostičkim parametrima ukazala je na značaj nove stratifikacije rizičnih grupa, koje zahtevaju promenu intenziteta hemioterapije. Praćenje MRB se pokazalo preciznim prediktivnim faktorom u nastanku recidiva bolesti. PR Projekat Ministarstva nauke Republike Srbije, br. 143051.
AB  - Introduction. Acute lymphoblastic leukaemia (ALL) is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD) follow up, in major percent responsible for relapse. Objective. The aim of the study was to detect the frequency of IgH and TCR gene rearrangements and their correlation with clinical parameters. Methods. Forty-one children with ALL were enrolled in the study group, with initial diagnosis of IgH and TCR gene rearrangements by polimerase chain reaction ( PCR). MRD follow-up was performed in induction phase when morphological remission was expected, and after intensive chemiotherapy. Results. In the study group IgH rearrangement was detected in 82.9% of children at the diagnosis, while TCR rearrangement was seen in 56.1%. On induction day 33, clonal IgH rearrangements persisted in 39% and TCR rearrangements in 36.5% of children. Conclusion. Molecular analysis of genetic alterations and their correlation with standard prognostic parameters show the importance of risk stratification revision which leads to new therapy intensification approach. MRD stands out as a precise predictive factor for the relapse of disease.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom
T1  - Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia
EP  - 390
IS  - 7-8
SP  - 384
VL  - 137
DO  - 10.2298/SARH0908384L
ER  - 

@article{
author = "Lazić, Jelena and Dokmanović, Lidija and Krstovski, Nada and Predojević, Jelica and Tošić, Nataša and Pavlović, Sonja and Janić, Dragana",
year = "2009",
abstract = "Uvod. Akutna limfoblastna leukemija (ALL) je maligna klonalna bolest i jedna od najčešćih neoplazmi dečjeg uzrasta. Primenom savremenih protokola postižu se visok stepen remisije i dugogodišnja stopa preživljavanja. Uvođenjem metoda molekularne genetike omogućeni su submikroskopska klasifikacija i praćenje minimalne rezidualne bolesti (MRB), odgovorne za nastanak recidiva. Cilj rada. Cilj rada je bilo ispitivanje učestalosti rearanžmana genskih lokusa za teške lance imunoglobulina (IgH) i T-ćelijski receptor (TCR) i njihova korelacija s kliničkim parametrima. Metode rada. Ispitano je 41 dete obolelo od ALL kojima je na dijagnozi rađena molekularna detekcija rearanžmana genskih lokusa za IgH i TCR metodom lančanog umnožavanja DNK (PCR). Posmatranje razvoja MRB je rađeno u indukcionoj fazi lečenja, kada se očekuje morfološki odgovor na terapiju. Rezultati. Rearanžman genskog lokusa za IgH zabeležen je kod 82,9%, a za TCR kod 56,1% ispitanika. Posle 33 dana indukcione terapije rearanžmani za IgH genski lokus su zabeleženi kod 39%, a za TCR kod 36,5% dece. Zaključak. Otkrivanje genetskih aberacija na molekularnom nivou i njihova korelacija sa standardnim prognostičkim parametrima ukazala je na značaj nove stratifikacije rizičnih grupa, koje zahtevaju promenu intenziteta hemioterapije. Praćenje MRB se pokazalo preciznim prediktivnim faktorom u nastanku recidiva bolesti. PR Projekat Ministarstva nauke Republike Srbije, br. 143051., Introduction. Acute lymphoblastic leukaemia (ALL) is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD) follow up, in major percent responsible for relapse. Objective. The aim of the study was to detect the frequency of IgH and TCR gene rearrangements and their correlation with clinical parameters. Methods. Forty-one children with ALL were enrolled in the study group, with initial diagnosis of IgH and TCR gene rearrangements by polimerase chain reaction ( PCR). MRD follow-up was performed in induction phase when morphological remission was expected, and after intensive chemiotherapy. Results. In the study group IgH rearrangement was detected in 82.9% of children at the diagnosis, while TCR rearrangement was seen in 56.1%. On induction day 33, clonal IgH rearrangements persisted in 39% and TCR rearrangements in 36.5% of children. Conclusion. Molecular analysis of genetic alterations and their correlation with standard prognostic parameters show the importance of risk stratification revision which leads to new therapy intensification approach. MRD stands out as a precise predictive factor for the relapse of disease.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom, Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia",
pages = "390-384",
number = "7-8",
volume = "137",
doi = "10.2298/SARH0908384L"
}

Lazić, J., Dokmanović, L., Krstovski, N., Predojević, J., Tošić, N., Pavlović, S.,& Janić, D.. (2009). Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 137(7-8), 384-390.
https://doi.org/10.2298/SARH0908384L

Lazić J, Dokmanović L, Krstovski N, Predojević J, Tošić N, Pavlović S, Janić D. Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom. in Srpski arhiv za celokupno lekarstvo. 2009;137(7-8):384-390.
doi:10.2298/SARH0908384L .

Lazić, Jelena, Dokmanović, Lidija, Krstovski, Nada, Predojević, Jelica, Tošić, Nataša, Pavlović, Sonja, Janić, Dragana, "Geni za imunoglobulin i T-ćelijski receptor kao molekularni markeri kod dece s akutnom limfoblastnom leukemijom" in Srpski arhiv za celokupno lekarstvo, 137, no. 7-8 (2009):384-390,
https://doi.org/10.2298/SARH0908384L . .

TY  - JOUR
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Krstovski, Nada
AU  - Zukić, Branka
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
PY  - 2008
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/309
AB  - Uvod. Tiopurin-S-metiltransferaza (TPMT ) je enzim koji katalizuje inaktivaciju merkaptopurina, leka koji se široko primenjuje u lečenju akutne limfoblastne leukemije (ALL) kod dece. Kada se osobe s nedostatkom TPMT leče standardnim dozama merkaptopurina, kod njih se razvija teška i po život opasna mijelotoksičnost. Cilj rada. Cilj rada je bio da se utvrdi da li kod dece s ALL koji su nosioci mutacije u genu za TPMT individualizovanjem doziranja merkaptopurina može da se smanji mijelotoksičnost terapije, te da li broj tandemskih ponovaka (engl. variable number of tandem repeats - VNTR) u promotoru gena za TPMT ima uticaja na efekte terapije merkaptopurinom. Metod rada Metodima lančane reakcije umnožavanja DNK (engl. polymerase chain reaction - PCR) ispitano je 50 nasumično odabrane dece lečene ALL IC-BFM 2002 protokolom na najčešće mutacije u genu za TPMT. Za 20 dece je PCR metodima određen VNTR genotip. Ispitanicima je tokom faze održavanja beležen broj nedelja kada su terapiju dobijali u punim ili smanjenim dozama, kao i broj nedelja bez terapije. Rezultati Među 50 dece bilo je 29 dečaka (58%) i 21 (42%) devojčica, uzrasta od 1,8 do 17,3 godine (medijana 6,2 godine). Utvrđeno je četvoro (8%) heterozigotnih nosilaca mutacija, kod kojih je otkrivena TPMT*3A varijanta. Posle 12, 14, 16 i 19 nedelja lečenja smanjenim dozama merkaptopurina bolesnici su, zbog dobrog podnošenja terapije, postepeno počeli da primaju punu dozu leka. Nije bilo odlaganja terapije. Smanjenje kumulativne doze merkaptopurina za bolesnike sa TPMT mutacijama bilo je 7,8%, 7,4%, 11,2% i 16,6%. Između dece bez TPMT mutacija i heterozigota nije za- beležena statistički značajna razlika u trajanju lečenja punim (53,6 nasuprot 55,7 nedelja) i smanjenim dozama merkaptopurina (19,9 nasuprot 15,2 nedelje). Otkrivenih VNTR bilo je između četiri i sedam. Većina bolesnika imala je različit broj VNTR na homolognim hromozomima. Najčešće uočen polimorfizam bio je VNTR*5. Nije zabeležena korelacija između nasleđivanja TPMT i VNTR genotipa. Zaključak Farmakogenetskim principima u lečenju ALL dece može se postići napredak u podnošenju lečenja merkaptopurinom.
AB  - INTRODUCTION Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients. OBJECTIVES To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene. To establish if variable number of tandem repeats (VNTR) genotype influences the treatment effects of MP. METHOD Fifty randomly selected patients treated according to ALL IC-BFM 2002 protocol were tested for most frequent TPMT gene mutations using PCR based methods. VNTR genotype was determined in 20 children by PCR methods. During the maintenance phase, we recorded the number of weeks when therapy was applied in either full doses, reduced doses or when patients were without any therapy. RESULTS Fifty children were examined, 29 boys (58%) and 21 girls (42%); age ranged from 1.8-17.3 years (median 6.2 years). Four patients (8%) were heterozygous for TPMT mutations, all of them carrying the TPMT*3A variant. After 12, 14, 16 and 19 weeks of therapy with reduced doses of MP, the patients switched to full doses due to good tolerance. There was no therapy omission. Cumulative dose of MP was reduced for 7.8%, 7.4%, 11.2% and 16.6%, respectively, in patients with TPMT mutations. No significant difference was found between children with no mutations and TPMT heterozygotes regarding full dose therapy (53.6 vs. 55.7 weeks, respectively) and reduced dose therapy (19.9 vs. 15.2 weeks respectively). The number of detected VNTRs ranged from four to seven. The majority of patients had different number of VNTRs on homologous chromosomes. Most frequently detected polymorphism was VNTR*5. No correlation was found between TPMT and VNTR genotype inheritance. CONCLUSION Obeying pharmacogenetic principles in the treatment of childhood ALL may improve the tolerance of therapy with MP.
PB  - Srpsko lekarsko društvo, Beograd
T2  - Srpski arhiv za celokupno lekarstvo
T1  - Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja
T1  - Importance of genotyping of Thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy
EP  - 616
IS  - 11-12
SP  - 609
VL  - 136
DO  - 10.2298/SARH0812609D
ER  - 

@article{
author = "Dokmanović, Lidija and Janić, Dragana and Krstovski, Nada and Zukić, Branka and Tošić, Nataša and Pavlović, Sonja",
year = "2008",
abstract = "Uvod. Tiopurin-S-metiltransferaza (TPMT ) je enzim koji katalizuje inaktivaciju merkaptopurina, leka koji se široko primenjuje u lečenju akutne limfoblastne leukemije (ALL) kod dece. Kada se osobe s nedostatkom TPMT leče standardnim dozama merkaptopurina, kod njih se razvija teška i po život opasna mijelotoksičnost. Cilj rada. Cilj rada je bio da se utvrdi da li kod dece s ALL koji su nosioci mutacije u genu za TPMT individualizovanjem doziranja merkaptopurina može da se smanji mijelotoksičnost terapije, te da li broj tandemskih ponovaka (engl. variable number of tandem repeats - VNTR) u promotoru gena za TPMT ima uticaja na efekte terapije merkaptopurinom. Metod rada Metodima lančane reakcije umnožavanja DNK (engl. polymerase chain reaction - PCR) ispitano je 50 nasumično odabrane dece lečene ALL IC-BFM 2002 protokolom na najčešće mutacije u genu za TPMT. Za 20 dece je PCR metodima određen VNTR genotip. Ispitanicima je tokom faze održavanja beležen broj nedelja kada su terapiju dobijali u punim ili smanjenim dozama, kao i broj nedelja bez terapije. Rezultati Među 50 dece bilo je 29 dečaka (58%) i 21 (42%) devojčica, uzrasta od 1,8 do 17,3 godine (medijana 6,2 godine). Utvrđeno je četvoro (8%) heterozigotnih nosilaca mutacija, kod kojih je otkrivena TPMT*3A varijanta. Posle 12, 14, 16 i 19 nedelja lečenja smanjenim dozama merkaptopurina bolesnici su, zbog dobrog podnošenja terapije, postepeno počeli da primaju punu dozu leka. Nije bilo odlaganja terapije. Smanjenje kumulativne doze merkaptopurina za bolesnike sa TPMT mutacijama bilo je 7,8%, 7,4%, 11,2% i 16,6%. Između dece bez TPMT mutacija i heterozigota nije za- beležena statistički značajna razlika u trajanju lečenja punim (53,6 nasuprot 55,7 nedelja) i smanjenim dozama merkaptopurina (19,9 nasuprot 15,2 nedelje). Otkrivenih VNTR bilo je između četiri i sedam. Većina bolesnika imala je različit broj VNTR na homolognim hromozomima. Najčešće uočen polimorfizam bio je VNTR*5. Nije zabeležena korelacija između nasleđivanja TPMT i VNTR genotipa. Zaključak Farmakogenetskim principima u lečenju ALL dece može se postići napredak u podnošenju lečenja merkaptopurinom., INTRODUCTION Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients. OBJECTIVES To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene. To establish if variable number of tandem repeats (VNTR) genotype influences the treatment effects of MP. METHOD Fifty randomly selected patients treated according to ALL IC-BFM 2002 protocol were tested for most frequent TPMT gene mutations using PCR based methods. VNTR genotype was determined in 20 children by PCR methods. During the maintenance phase, we recorded the number of weeks when therapy was applied in either full doses, reduced doses or when patients were without any therapy. RESULTS Fifty children were examined, 29 boys (58%) and 21 girls (42%); age ranged from 1.8-17.3 years (median 6.2 years). Four patients (8%) were heterozygous for TPMT mutations, all of them carrying the TPMT*3A variant. After 12, 14, 16 and 19 weeks of therapy with reduced doses of MP, the patients switched to full doses due to good tolerance. There was no therapy omission. Cumulative dose of MP was reduced for 7.8%, 7.4%, 11.2% and 16.6%, respectively, in patients with TPMT mutations. No significant difference was found between children with no mutations and TPMT heterozygotes regarding full dose therapy (53.6 vs. 55.7 weeks, respectively) and reduced dose therapy (19.9 vs. 15.2 weeks respectively). The number of detected VNTRs ranged from four to seven. The majority of patients had different number of VNTRs on homologous chromosomes. Most frequently detected polymorphism was VNTR*5. No correlation was found between TPMT and VNTR genotype inheritance. CONCLUSION Obeying pharmacogenetic principles in the treatment of childhood ALL may improve the tolerance of therapy with MP.",
publisher = "Srpsko lekarsko društvo, Beograd",
journal = "Srpski arhiv za celokupno lekarstvo",
title = "Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja, Importance of genotyping of Thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy",
pages = "616-609",
number = "11-12",
volume = "136",
doi = "10.2298/SARH0812609D"
}

Dokmanović, L., Janić, D., Krstovski, N., Zukić, B., Tošić, N.,& Pavlović, S.. (2008). Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja. in Srpski arhiv za celokupno lekarstvo
Srpsko lekarsko društvo, Beograd., 136(11-12), 609-616.
https://doi.org/10.2298/SARH0812609D

Dokmanović L, Janić D, Krstovski N, Zukić B, Tošić N, Pavlović S. Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja. in Srpski arhiv za celokupno lekarstvo. 2008;136(11-12):609-616.
doi:10.2298/SARH0812609D .

Dokmanović, Lidija, Janić, Dragana, Krstovski, Nada, Zukić, Branka, Tošić, Nataša, Pavlović, Sonja, "Značaj određivanja genotipa Tiopurin-S-metiltransferaze kod dece s akutnom limfoblastnom leukemijom tokom terapije održavanja" in Srpski arhiv za celokupno lekarstvo, 136, no. 11-12 (2008):609-616,
https://doi.org/10.2298/SARH0812609D . .

TY  - CONF
AU  - Dokmanović, Lidija
AU  - Janić, Dragana
AU  - Krstovski, Nada
AU  - Lazić, Jelena
AU  - Rodić, Predrag
AU  - Pavlović, Sonja
PY  - 2007
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/274
PB  - Wiley-Liss, Hoboken
C3  - Pediatric Blood & Cancer
T1  - Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia
EP  - 424
IS  - 4
SP  - 424
VL  - 49
UR  - https://hdl.handle.net/21.15107/rcub_imagine_274
ER  - 

@conference{
author = "Dokmanović, Lidija and Janić, Dragana and Krstovski, Nada and Lazić, Jelena and Rodić, Predrag and Pavlović, Sonja",
year = "2007",
publisher = "Wiley-Liss, Hoboken",
journal = "Pediatric Blood & Cancer",
title = "Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia",
pages = "424-424",
number = "4",
volume = "49",
url = "https://hdl.handle.net/21.15107/rcub_imagine_274"
}

Dokmanović, L., Janić, D., Krstovski, N., Lazić, J., Rodić, P.,& Pavlović, S.. (2007). Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia. in Pediatric Blood & Cancer
Wiley-Liss, Hoboken., 49(4), 424-424.
https://hdl.handle.net/21.15107/rcub_imagine_274

Dokmanović L, Janić D, Krstovski N, Lazić J, Rodić P, Pavlović S. Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia. in Pediatric Blood & Cancer. 2007;49(4):424-424.
https://hdl.handle.net/21.15107/rcub_imagine_274 .

Dokmanović, Lidija, Janić, Dragana, Krstovski, Nada, Lazić, Jelena, Rodić, Predrag, Pavlović, Sonja, "Importance of genotypic analysis of thiopurine S-methyltransferase in children with acute lymphoblastic leukemia" in Pediatric Blood & Cancer, 49, no. 4 (2007):424-424,
https://hdl.handle.net/21.15107/rcub_imagine_274 .

TY  - JOUR
AU  - Dokmanović, Lidija
AU  - Urosević, Jelena
AU  - Janić, Dragana
AU  - Jovanović, Nada
AU  - Petručev, Branka
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
PY  - 2006
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/250
AB  - Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. It is now well established that interindividual variation in sensitivity to thiopurines can be the result of the presence of genetic polymorphisms in the TPMT gene. The aim of this study was to determine the frequency and type of TPMT polymorphisms in the population of Serbia and Montenegro and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Blood samples from 100 healthy adults and 100 children with ALL were analyzed for common mutations in the TPMT gene using polymerase chain reaction-based assays. The results revealed that allelic frequencies were 0.2% for TPMT*2, 3.2% for TPMT*3A, and 0.5% for TPMT*3B. A rare TPMT*3B allele was detected in 2 families. No TPMT*3C allele was found. The general pattern of TPMT-variant allele distribution as well as their frequencies in the population of Serbia and Montenegro, is similar to those determined for other Slavic and Mediterranean populations. The ability to tolerate 6-mercaptopurine (6-MP) -based maintenance therapy was used as a surrogate marker of hematologic toxicity. In the study of 50 patients with childhood ALL treated according to the BFM-like protocol, it was found that even TPMT-heterozygous patients are at greater risk of thiopurine drug-related leukopenia (mean duration of period when children missed therapy as a result of leukopenia for TPMT-heterozygous patients was 11.3 weeks vs 3.4 weeks for wild-type genotype patients, P  lt  0.01). In another group of 50 patients, the TPMT genotype was determined prospectively. The therapy protocol was modified considering their TPMT genotype. Administering reduced 6-MP dosages in the initial phase of maintenance allowed TPMT-heterozygous patients to later receive full protocol doses of both 6-MP and nonthiopurine therapy without omitting therapy resulting from myelotoxicity. These results justify performing TPMT genotyping before initiating thiopurine therapy in all children with ALL to minimize consequent toxicity.
PB  - Lippincott Williams & Wilkins, Philadelphia
T2  - Therapeutic Drug Monitoring
T1  - Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia
EP  - 806
IS  - 6
SP  - 800
VL  - 28
DO  - 10.1097/01.ftd.0000249947.17676.92
ER  - 

@article{
author = "Dokmanović, Lidija and Urosević, Jelena and Janić, Dragana and Jovanović, Nada and Petručev, Branka and Tošić, Nataša and Pavlović, Sonja",
year = "2006",
abstract = "Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. It is now well established that interindividual variation in sensitivity to thiopurines can be the result of the presence of genetic polymorphisms in the TPMT gene. The aim of this study was to determine the frequency and type of TPMT polymorphisms in the population of Serbia and Montenegro and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Blood samples from 100 healthy adults and 100 children with ALL were analyzed for common mutations in the TPMT gene using polymerase chain reaction-based assays. The results revealed that allelic frequencies were 0.2% for TPMT*2, 3.2% for TPMT*3A, and 0.5% for TPMT*3B. A rare TPMT*3B allele was detected in 2 families. No TPMT*3C allele was found. The general pattern of TPMT-variant allele distribution as well as their frequencies in the population of Serbia and Montenegro, is similar to those determined for other Slavic and Mediterranean populations. The ability to tolerate 6-mercaptopurine (6-MP) -based maintenance therapy was used as a surrogate marker of hematologic toxicity. In the study of 50 patients with childhood ALL treated according to the BFM-like protocol, it was found that even TPMT-heterozygous patients are at greater risk of thiopurine drug-related leukopenia (mean duration of period when children missed therapy as a result of leukopenia for TPMT-heterozygous patients was 11.3 weeks vs 3.4 weeks for wild-type genotype patients, P  lt  0.01). In another group of 50 patients, the TPMT genotype was determined prospectively. The therapy protocol was modified considering their TPMT genotype. Administering reduced 6-MP dosages in the initial phase of maintenance allowed TPMT-heterozygous patients to later receive full protocol doses of both 6-MP and nonthiopurine therapy without omitting therapy resulting from myelotoxicity. These results justify performing TPMT genotyping before initiating thiopurine therapy in all children with ALL to minimize consequent toxicity.",
publisher = "Lippincott Williams & Wilkins, Philadelphia",
journal = "Therapeutic Drug Monitoring",
title = "Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia",
pages = "806-800",
number = "6",
volume = "28",
doi = "10.1097/01.ftd.0000249947.17676.92"
}

Dokmanović, L., Urosević, J., Janić, D., Jovanović, N., Petručev, B., Tošić, N.,& Pavlović, S.. (2006). Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia. in Therapeutic Drug Monitoring
Lippincott Williams & Wilkins, Philadelphia., 28(6), 800-806.
https://doi.org/10.1097/01.ftd.0000249947.17676.92

Dokmanović L, Urosević J, Janić D, Jovanović N, Petručev B, Tošić N, Pavlović S. Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia. in Therapeutic Drug Monitoring. 2006;28(6):800-806.
doi:10.1097/01.ftd.0000249947.17676.92 .

Dokmanović, Lidija, Urosević, Jelena, Janić, Dragana, Jovanović, Nada, Petručev, Branka, Tošić, Nataša, Pavlović, Sonja, "Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia" in Therapeutic Drug Monitoring, 28, no. 6 (2006):800-806,
https://doi.org/10.1097/01.ftd.0000249947.17676.92 . .