Importantly, studies have shown that mutations in epigenetic modifiers, including DNMT3A and IDH1/IDH2, occur in early pre-leukemic HSCs (29, 34, 35), while signaling pathway mutations in genes that confer proliferative advantage, such as NPM1 (nucleophosmin 1), FLT3-ITD (internal tandem duplication of the FLT3 gene), and KRAS/NRAS, are acquired later during the development of AML (36). This evidence concerns the gene DNMT3A and acute myeloid leukemia.