We establish herein a novel protective role for miR-196b in HSPCs that delays AML development driven by coincident Dnmt3a and Flt3ITD mutations whereby Dnmt3a/Flt3-mutant mice with deletion of miR-196b succumb to AML faster than Dnmt3a/Flt3-mutant mice with endogenous miR-196b. Here, DNMT3A is linked to acute myeloid leukemia.