PU.1 and MYC transcriptional network defines a synergist drug response to combined KIT and LSD1 inhibition in acute myeloid leukemia

KIT mutant acute myeloid leukemia (AML) confers a worse prognosis for patients in a subtype of AML that has an otherwise favorable outcome. Here, we demonstrate that lysine specific demethylase 1 (LSD1) inhibition potentiates cytotoxic effect of KIT inhibition in KIT mutant AML. We identified loss of PU.1 binding to be a key feature of LSD1 inhibition, contributing to a decrease in MYC enhancer and promoter activation. This loss of MYC enhancer/promoter activation results in decreased MYC expression and binding at proliferation associated promoters decreasing cell cycle progression. Our results nominate PI3K/AKT pathway inactivation as a key feature of KIT and LSD1 inhibition ultimately leading to decreased MYC and blocking LSD1 from activating its targets. Our findings support a mechanistic model for synergy between dual KIT and LSD1 inhibition and suggest this combination should be investigated in a clinical setting. Kasumi-1 and patient sample cells were analyzed by multi-omic profiling including bulk RNA seq, scRNAseq, CUT&Tag, CUT&RUN, and ATACseq to understand the mechanism of KIT and LSD1 inhibitor synergy.