By generating the conditional DKI mouse model, we discovered that cooperation of Dnmt3a R878H and Nras G12D could lead to a much earlier onset and more severe AML characterized by significantly increased WBCs, elevated immature cells, splenomegaly and shortened survival time, compared with Dnmt3aR878H/+ or NrasG12D/+ KI mice. This evidence concerns the gene DNMT3A and acute myeloid leukemia.