TY  - JOUR
AU  - Hackl, Hubert
AU  - Steinleitner, Katarina
AU  - Lind, Karin
AU  - Hofer, Sybille
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
AU  - Suvajdžić, Nada
AU  - Sill, Heinz
AU  - Wieser, Rotraud
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/857
AB  - Some 50 – 80% of patients with acute myeloid leukemia (AML)
achieve a complete remission with contemporary chemotherapy protocols, yet the majority of them eventually relapse
with resistant disease: some patients no longer respond to
chemotherapy at disease recurrence; others accomplish
second and even third remissions whose decreasing duration nevertheless indicates that the pool of residual leukemic
cells, i.e. of cells that persisted during treatment with cytotoxic
drugs, increases with every round of therapy [1]. Either of
these clinical courses therefore refl ects an enhanced chemotherapy resistance of leukemic cells at relapse as compared to
the cell population at diagnosis. Molecular changes enabling
malignant cells to survive exposure to cytotoxic drugs may
already have been present in a subset of the leukemic cell
population at presentation, or may emerge during treatment
[2,3], but in any case are thought to be selected as a consequence of drug therapy, and to play a major role in therapy
resistance at relapse. Remarkably, however, even though
various types of molecular alterations may be acquired at
relapse, neither specifi c cytogenetic alterations nor functionally relevant point mutations as identifi ed by whole genome
sequencing were associated with relapse in a recurrent manner [2,3]. Certain copy number variations and known AML
associated point mutations were newly present at relapse in
small proportions of patients (usually  10%), but the latter
were lost in other patients, indicating that they are unlikely to
represent drivers of therapy resistance at disease recurrence
[4]. Th ese fi ndings could either indicate that chemotherapy
resistance at relapse is acquired through a large variety of different mechanisms, or that molecular changes of other types
than those mentioned above are of more general relevance
in this context. Indeed, an earlier study has suggested that
the expression of specifi c genes may change in a consistent
manner between diagnosis and relapse of AML [5]. However,
only a limited number of genes and mostly unpaired samples
were probed in this investigation. Th erefore, in the present
study, genes whose expression changed in a relapse-specifi c
manner were sought in a set of paired AML samples and on
a genome-wide scale. To limit the genetic heterogeneity of
the study population, only samples from patients with cytogenetically normal (CN) AML were used.
PB  - Taylor & Francis Ltd, Abingdon
T2  - Leukemia & Lymphoma
T1  - A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes
EP  - 1128
IS  - 4
SP  - 1126
VL  - 56
DO  - 10.3109/10428194.2014.944523
ER  - 

@article{
author = "Hackl, Hubert and Steinleitner, Katarina and Lind, Karin and Hofer, Sybille and Tošić, Nataša and Pavlović, Sonja and Suvajdžić, Nada and Sill, Heinz and Wieser, Rotraud",
year = "2015",
abstract = "Some 50 – 80% of patients with acute myeloid leukemia (AML)
achieve a complete remission with contemporary chemotherapy protocols, yet the majority of them eventually relapse
with resistant disease: some patients no longer respond to
chemotherapy at disease recurrence; others accomplish
second and even third remissions whose decreasing duration nevertheless indicates that the pool of residual leukemic
cells, i.e. of cells that persisted during treatment with cytotoxic
drugs, increases with every round of therapy [1]. Either of
these clinical courses therefore refl ects an enhanced chemotherapy resistance of leukemic cells at relapse as compared to
the cell population at diagnosis. Molecular changes enabling
malignant cells to survive exposure to cytotoxic drugs may
already have been present in a subset of the leukemic cell
population at presentation, or may emerge during treatment
[2,3], but in any case are thought to be selected as a consequence of drug therapy, and to play a major role in therapy
resistance at relapse. Remarkably, however, even though
various types of molecular alterations may be acquired at
relapse, neither specifi c cytogenetic alterations nor functionally relevant point mutations as identifi ed by whole genome
sequencing were associated with relapse in a recurrent manner [2,3]. Certain copy number variations and known AML
associated point mutations were newly present at relapse in
small proportions of patients (usually  10%), but the latter
were lost in other patients, indicating that they are unlikely to
represent drivers of therapy resistance at disease recurrence
[4]. Th ese fi ndings could either indicate that chemotherapy
resistance at relapse is acquired through a large variety of different mechanisms, or that molecular changes of other types
than those mentioned above are of more general relevance
in this context. Indeed, an earlier study has suggested that
the expression of specifi c genes may change in a consistent
manner between diagnosis and relapse of AML [5]. However,
only a limited number of genes and mostly unpaired samples
were probed in this investigation. Th erefore, in the present
study, genes whose expression changed in a relapse-specifi c
manner were sought in a set of paired AML samples and on
a genome-wide scale. To limit the genetic heterogeneity of
the study population, only samples from patients with cytogenetically normal (CN) AML were used.",
publisher = "Taylor & Francis Ltd, Abingdon",
journal = "Leukemia & Lymphoma",
title = "A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes",
pages = "1128-1126",
number = "4",
volume = "56",
doi = "10.3109/10428194.2014.944523"
}

Hackl, H., Steinleitner, K., Lind, K., Hofer, S., Tošić, N., Pavlović, S., Suvajdžić, N., Sill, H.,& Wieser, R.. (2015). A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes. in Leukemia & Lymphoma
Taylor & Francis Ltd, Abingdon., 56(4), 1126-1128.
https://doi.org/10.3109/10428194.2014.944523

Hackl H, Steinleitner K, Lind K, Hofer S, Tošić N, Pavlović S, Suvajdžić N, Sill H, Wieser R. A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes. in Leukemia & Lymphoma. 2015;56(4):1126-1128.
doi:10.3109/10428194.2014.944523 .

Hackl, Hubert, Steinleitner, Katarina, Lind, Karin, Hofer, Sybille, Tošić, Nataša, Pavlović, Sonja, Suvajdžić, Nada, Sill, Heinz, Wieser, Rotraud, "A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes" in Leukemia & Lymphoma, 56, no. 4 (2015):1126-1128,
https://doi.org/10.3109/10428194.2014.944523 . .

TY  - JOUR
AU  - Milosević, Jelena D.
AU  - Puda, Ana
AU  - Malcovati, Luca
AU  - Berg, Tiina
AU  - Hofbauer, Michael
AU  - Stukalov, Alexey
AU  - Klampfl, Thorsten
AU  - Harutyunyan, Ashot S.
AU  - Gisslinger, Heinz
AU  - Gisslinger, Bettina
AU  - Burjanivova, Tatiana
AU  - Rumi, Elisa
AU  - Pietra, Daniela
AU  - Elena, Chiara
AU  - Vannucchi, Alessandro M.
AU  - Doubek, Michael
AU  - Dvorakova, Dana
AU  - Robesova, Blanka
AU  - Wieser, Rotraud
AU  - Koller, Elisabeth
AU  - Suvajdžić, Nada
AU  - Tomin, Dragica
AU  - Tošić, Nataša
AU  - Colinge, Jacques
AU  - Racil, Zdenek
AU  - Steurer, Michael
AU  - Pavlović, Sonja
AU  - Cazzola, Mario
AU  - Kralovics, Robert
PY  - 2012
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/590
AB  - The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012.
PB  - Wiley, Hoboken
T2  - American Journal of Hematology
T1  - Clinical significance of genetic aberrations in secondary acute myeloid leukemia
EP  - 1016
IS  - 11
SP  - 1010
VL  - 87
DO  - 10.1002/ajh.23309
ER  - 

@article{
author = "Milosević, Jelena D. and Puda, Ana and Malcovati, Luca and Berg, Tiina and Hofbauer, Michael and Stukalov, Alexey and Klampfl, Thorsten and Harutyunyan, Ashot S. and Gisslinger, Heinz and Gisslinger, Bettina and Burjanivova, Tatiana and Rumi, Elisa and Pietra, Daniela and Elena, Chiara and Vannucchi, Alessandro M. and Doubek, Michael and Dvorakova, Dana and Robesova, Blanka and Wieser, Rotraud and Koller, Elisabeth and Suvajdžić, Nada and Tomin, Dragica and Tošić, Nataša and Colinge, Jacques and Racil, Zdenek and Steurer, Michael and Pavlović, Sonja and Cazzola, Mario and Kralovics, Robert",
year = "2012",
abstract = "The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012.",
publisher = "Wiley, Hoboken",
journal = "American Journal of Hematology",
title = "Clinical significance of genetic aberrations in secondary acute myeloid leukemia",
pages = "1016-1010",
number = "11",
volume = "87",
doi = "10.1002/ajh.23309"
}

Milosević, J. D., Puda, A., Malcovati, L., Berg, T., Hofbauer, M., Stukalov, A., Klampfl, T., Harutyunyan, A. S., Gisslinger, H., Gisslinger, B., Burjanivova, T., Rumi, E., Pietra, D., Elena, C., Vannucchi, A. M., Doubek, M., Dvorakova, D., Robesova, B., Wieser, R., Koller, E., Suvajdžić, N., Tomin, D., Tošić, N., Colinge, J., Racil, Z., Steurer, M., Pavlović, S., Cazzola, M.,& Kralovics, R.. (2012). Clinical significance of genetic aberrations in secondary acute myeloid leukemia. in American Journal of Hematology
Wiley, Hoboken., 87(11), 1010-1016.
https://doi.org/10.1002/ajh.23309

Milosević JD, Puda A, Malcovati L, Berg T, Hofbauer M, Stukalov A, Klampfl T, Harutyunyan AS, Gisslinger H, Gisslinger B, Burjanivova T, Rumi E, Pietra D, Elena C, Vannucchi AM, Doubek M, Dvorakova D, Robesova B, Wieser R, Koller E, Suvajdžić N, Tomin D, Tošić N, Colinge J, Racil Z, Steurer M, Pavlović S, Cazzola M, Kralovics R. Clinical significance of genetic aberrations in secondary acute myeloid leukemia. in American Journal of Hematology. 2012;87(11):1010-1016.
doi:10.1002/ajh.23309 .

Milosević, Jelena D., Puda, Ana, Malcovati, Luca, Berg, Tiina, Hofbauer, Michael, Stukalov, Alexey, Klampfl, Thorsten, Harutyunyan, Ashot S., Gisslinger, Heinz, Gisslinger, Bettina, Burjanivova, Tatiana, Rumi, Elisa, Pietra, Daniela, Elena, Chiara, Vannucchi, Alessandro M., Doubek, Michael, Dvorakova, Dana, Robesova, Blanka, Wieser, Rotraud, Koller, Elisabeth, Suvajdžić, Nada, Tomin, Dragica, Tošić, Nataša, Colinge, Jacques, Racil, Zdenek, Steurer, Michael, Pavlović, Sonja, Cazzola, Mario, Kralovics, Robert, "Clinical significance of genetic aberrations in secondary acute myeloid leukemia" in American Journal of Hematology, 87, no. 11 (2012):1010-1016,
https://doi.org/10.1002/ajh.23309 . .