P300/CBP inhibition with gilteritinib and venetoclax targets leukemia stem cells in epigenetic mutant AML [ChIP-Seq]

Acute myeloid leukemia (AML) is a fatal blood cancer with cytotoxic chemotherapy offering at best 25% 5-year survival. While targeted BCL2 and FLT3 inhibitors venetoclax and gilteritinib are used upfront in the treatment of a subset of adult AML patients and help to extend the survival of some patients, a curative treatment combination with minimal side effects has yet to be discovered. 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 DNMT3A/FLT3-mutant AML by impairing pro-oncogenic survival and proliferation factors to effectively block leukemogenesis. This work identifies potential clinical utility of a novel, targeted, triplet combination therapy for treatment of AML. Overall design: H3K27ac ChIP-seq profiling of Dnmt3a/Flt3 and Tet2/Flt3 mutant murine AML cells after 1 hours of in vitro p300/CBP inhibitor treatment with CCS1477.