We find that use of the dual histone acetyltransferase p300/CBP bromodomain inhibitor CCS1477 (inobrodib), together with venetoclax and gilteritinib, virtually eliminates leukemia stem cells in an aggressive preclinical model of <i>DNMT3A/FLT3</i>-mutant AML by impairing pro-oncogenic survival and proliferation factors to effectively block leukemogenesis. This evidence concerns the gene EP300 and acute myeloid leukemia.