Recent studies have identified recurrent mutations in genes that encode proteins crucial in the epigenetic regulation of gene transcription in hematologic malignancies. Somatic mutations in epigenetic modifiers, including IDH1, IDH2, TET2, DNAMT3A, ASXL1, MLL and EZH2 are enriched in patients with acute myeloid leukemia (AML), especially those with intermediate-risk cytogenetics. Here we describe the clinic-biologic features of AML patients with these mutations, their prognostic relevance and potential as therapeutic targets. The epigenetic alterations are present as the early pre-leukemic events and usually remain stable during disease evolution, implying the potential to be biomarkers for minimal residual disease monitoring. The high frequency of mutations in epigenetic modifiers and their prognostic implications shed light on the development of epigenetic therapy.

Abnormal epigenetic patterning commonly is observed in cancer, including the myeloid malignancies acute myeloid leukemia and myelodysplastic syndromes. However, despite the universal nature of epigenetic deregulation, specific subtypes of myeloid disorders are associated with distinct epigenetic profiles, which accurately reflect the biologic heterogeneity of these disorders. In addition, mutations and genetic alterations of epigenetic-modifying enzymes frequently have been reported in these myeloid malignancies, emphasizing the importance of epigenetic deregulation in the initiation, progression, and outcome of these disorders. These aberrant epigenetic modifiers have become new targets for drug design, because their inhibition can potentially reverse the altered epigenetic landscapes that contribute to the development of the leukemia. In this review, we provide an overview of the role of epigenetic deregulation in leukemic transformation and their potential for therapeutic targeting.