DNA Methylation Alterations in Acute Myeloid Leukemia: Therapeutic Potential

Acute myeloid leukemia (AML) is a complex and heterogeneous disease characterized by different genetic or cytogenetic abnormalities. Additionally, epigenetic alterations are considered to play critical roles in AML pathogenesis. Epigenetic events are reversible, which could make them appropriate therapeutic targets. Epigenetic changes could also function as diagnostic and prognostic biomarkers. DNA methylation is an important mechanism of epigenetic regulation with significant roles in normal hematopoiesis. DNA methylation is regulated by DNA methyltransferases (DNMTs), ten-eleven translocation methylcytosine dioxygenases (TETs), and isocitrate dehydrogenases (IDHs). Genetic alterations of these regulators disrupt normal hematopoiesis. Abnormalities in DNA methylation affect the expression of tumor suppressor genes, DNA repair genes or oncogenes, which lead to AML initiation and progression. The hypomethylating agents (HMAs), decitabine and azacitidine, and IDH inhibitors (ivosidenib, enasidenib) have been used in the treatment of AML as epi-drugs. Combinational approaches including epi-drugs and targeted approaches are still under investigation and the discovery of new epi-targets could lead to novel therapeutics. In this study, the recent knowledge of DNA methylation in normal hematopoiesis and AML pathogenesis will be discussed. The most relevant clinical data regarding the roles of aberrant DNA methylation and the current epigenetic therapy targeting DNA methylation in AML will be summarized.