Genes encoding epigenetic modifiers are among the most frequently mutated in hematopoietic malignancies.1,2 It has been suggested that dysfunctions in these genes, such as TET2, DNMT3A, and IDH1/2, promote leukemogenesis by blocking the differentiation of hematopoietic stem and progenitor cells (HSPCs).3–7 Our previous studies identified Mixed Lineage Leukemia 3 (MLL3, officially known as KMT2C) on chromosome 7q as a tumor suppressor gene.8 Haploinsufficiency of Mll3 impairs HSPC differentiation and leads to (myelodysplastic syndrome) MDS-like phenotypes. Here, DNMT3A is linked to myelodysplastic syndrome.