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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182150 | GEO | 2022/05/29

REPOSITORIES: GEO

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Project description:Clinical responses to kinase inhibitor therapy in acute myeloid leukemia (AML) are limited by the inevitable development of resistance. A major contributor to resistance is early epigenetic adaptation, leading to persistence of a small number of leukemia cells. Here we show that inhibition of the epigenetic regulator lysine-specific deme-thylase 1 (LSD1) augments the response to inhibitors of the FLT3 kinase in AML. We demonstrate that combined FLT3 and LSD1 inhibition results in synergistic cell death of FLT3-mutant AML cells via proliferative arrest and apoptosis. The drug combination synergistically activates a pro-differentiative epigenetic and transcriptional program while simultaneously suppressing the activity of MYC target genes. High resolution multi-modal epigenetic analyses revealed that combined FLT3 and LSD1 resulted in the suppression of MYC-bound promoters and the activation of PU.1-bound enhanc-ers. Forced expression of MYC partially abrogated the drug effect, and regulon en-richment analysis in primary AML samples nominated STAT5 as a putative regulator of MYC gene expression. STAT5 is highly bound to the MYC blood super-enhancer and inhibition of FLT3 results in a loss of STAT5 binding and a loss of super enhancer acti-vation. Furthermore, knockdown of STAT5 augments LSD1-inhibitor induced cell death. LSD1 inhibition also directly represses MYC target genes which show specific accumulation of the repressive LSD1 substrate H3K9me1. We validated these findings in 67 primary AML samples including 19 FLT3-ITD positive AML samples, with the vast majority demonstrating improved responses with the drug combination. High MYC regulon activity was a predictor of response to the drug combination and RNA-seq on drug treated AML samples revealed suppression of MYC target genes. Finally, single cell ATAC seq on primary AML blasts treated ex-vivo with combined FLT3 and LSD1 inhibition results in a shift from MYC super enhancer-high to a MYC super enhancer-low cell state. Collectively, these studies provide preclinical rationale for the investiga-tion of dual FLT3 and LSD1 inhibition in clinical trial.

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

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