Myelodysplastic syndromes (MDS) are clonal diseases of the elderly characterized by chronic cytopenias, dysplasia, and a variable risk of progression to acute myeloid leukemia (AML). Aberrant methylation of tumor suppressor gene promoters has been established for many years and recently tracked to the most immature cells of MDS, suggesting that these alterations are drivers of MDS pathogenesis. In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation, and in covalent histone modifications have been reported in myeloid malignancies, including MDS. Whole-genome epigenetic profiles of MDS are also emerging. In parallel with these advances in the molecular pathogenesis of MDS, clinical trials have established hypomethylating agents as the mainstay of therapy in the advanced forms of the disease. In this review, we summarize the current understanding of the molecular machinery involved in epigenetic regulation, discuss how epigenetic alterations arise in MDS and contribute to its pathogenesis, then discuss the mode of action of hypomethylating agents in MDS.Leukemia accepted article preview online, 19 November 2013.
- myelodysplastic syndromes (MDS)