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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 theJARID2gene—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 asEZH2,AEBP2, andSUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses ofJARID2andAEBP2. We observed frequent codeletion ofAEBP2andETV6, and similarly,SUZ12andNF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex memberSUZ12. 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. © 2011 Wiley Periodicals, Inc.