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In recent studies on acute myeloid leukemia (AML), genes involving DNA methylation (DNMT3A, IDH1/2, TET2) were identified as frequently mutated. Around 17% of AML patients were found to have a mutation in isocitrate dehydrogenase-1 or -2 (IDH1/2). In these patients, 2-hydroxylglutarate (2-HG), which is generated from a neomorphic activity of mutant IDH1/2, accumulates and inhibits DNA hydroxylmethylation mediated by TETfamily proteins. Interestingly, mutations in the de novoDNA methyltransferase 3A (DNMT3A) and IDH1/2mutations co–occur in a statistically significant portion of AML patients. In current known mouse models, neither Dnmt3aknockout (KO) and IDH1/2mutation alone initiates overt hematopoietic malignancy, leading to our hypothesis that Dnmt3aand IDH1/2mutations may act synergistically to initiate hematopoietic malignancy.