TY  - JOUR
AU  - Puda, Ana
AU  - Milosević, Jelena D.
AU  - Berg, Tiina
AU  - Klampfl, Thorsten
AU  - Harutyunyan, Ashot S.
AU  - Gisslinger, Bettina
AU  - Rumi, Elisa
AU  - Pietra, Daniela
AU  - Malcovati, Luca
AU  - Elena, Chiara
AU  - Doubek, Michael
AU  - Steurer, Michael
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
AU  - Guglielmelli, Paola
AU  - Pieri, Lisa
AU  - Vannucchi, Alessandro M.
AU  - Gisslinger, Heinz
AU  - Cazzola, Mario
AU  - Kralovics, Robert
PY  - 2012
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/601
AB  - Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 genemember of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders. Am. J. Hematol. 2012.
PB  - Wiley, Hoboken
T2  - American Journal of Hematology
T1  - Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies
EP  - 250
IS  - 3
SP  - 245
VL  - 87
DO  - 10.1002/ajh.22257
ER  - 

@article{
author = "Puda, Ana and Milosević, Jelena D. and Berg, Tiina and Klampfl, Thorsten and Harutyunyan, Ashot S. and Gisslinger, Bettina and Rumi, Elisa and Pietra, Daniela and Malcovati, Luca and Elena, Chiara and Doubek, Michael and Steurer, Michael and Tošić, Nataša and Pavlović, Sonja and Guglielmelli, Paola and Pieri, Lisa and Vannucchi, Alessandro M. and Gisslinger, Heinz and Cazzola, Mario and Kralovics, Robert",
year = "2012",
abstract = "Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 genemember of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders. Am. J. Hematol. 2012.",
publisher = "Wiley, Hoboken",
journal = "American Journal of Hematology",
title = "Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies",
pages = "250-245",
number = "3",
volume = "87",
doi = "10.1002/ajh.22257"
}

Puda, A., Milosević, J. D., Berg, T., Klampfl, T., Harutyunyan, A. S., Gisslinger, B., Rumi, E., Pietra, D., Malcovati, L., Elena, C., Doubek, M., Steurer, M., Tošić, N., Pavlović, S., Guglielmelli, P., Pieri, L., Vannucchi, A. M., Gisslinger, H., Cazzola, M.,& Kralovics, R.. (2012). Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies. in American Journal of Hematology
Wiley, Hoboken., 87(3), 245-250.
https://doi.org/10.1002/ajh.22257

Puda A, Milosević JD, Berg T, Klampfl T, Harutyunyan AS, Gisslinger B, Rumi E, Pietra D, Malcovati L, Elena C, Doubek M, Steurer M, Tošić N, Pavlović S, Guglielmelli P, Pieri L, Vannucchi AM, Gisslinger H, Cazzola M, Kralovics R. Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies. in American Journal of Hematology. 2012;87(3):245-250.
doi:10.1002/ajh.22257 .

Puda, Ana, Milosević, Jelena D., Berg, Tiina, Klampfl, Thorsten, Harutyunyan, Ashot S., Gisslinger, Bettina, Rumi, Elisa, Pietra, Daniela, Malcovati, Luca, Elena, Chiara, Doubek, Michael, Steurer, Michael, Tošić, Nataša, Pavlović, Sonja, Guglielmelli, Paola, Pieri, Lisa, Vannucchi, Alessandro M., Gisslinger, Heinz, Cazzola, Mario, Kralovics, Robert, "Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies" in American Journal of Hematology, 87, no. 3 (2012):245-250,
https://doi.org/10.1002/ajh.22257 . .

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 . .