Title |
Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies
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Published in |
American Journal of Hematology, December 2011
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DOI | 10.1002/ajh.22257 |
Pubmed ID | |
Authors |
Ana Puda, Jelena D. Milosevic, Tiina Berg, Thorsten Klampfl, Ashot S. Harutyunyan, Bettina Gisslinger, Elisa Rumi, Daniela Pietra, Luca Malcovati, Chiara Elena, Michael Doubek, Michael Steurer, Natasa Tosic, Sonja Pavlovic, Paola Guglielmelli, Lisa Pieri, Alessandro M. Vannucchi, Heinz Gisslinger, Mario Cazzola, Robert Kralovics |
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 gene--member 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. |
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