ABSTRACT
Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood super-enhancer, suppressing super-enhancer activation as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies provide preclinical rationale for the investigation of dual FLT3/LSD1 inhibition in a clinical trial.
Competing Interest Statement
W.M. Yashar is a former employee of Abreos Biosciences, Inc. and was compensated in part with common stock options. Pursuant to the merger and reorganization agreement between Abreos Biosciences, Inc. and Fimafeng, Inc., W.M.Y. surrendered all of his common stock options in 03/2021. J.E. Maxson discloses a collaboration with Ionis pharmaceuticals, research funding from Gilead Sciences, research funding from Kura Oncology and research funding from Blueprint Medicines. J.W. Tyner has received research support from Acerta, Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Kronos, Meryx, Petra, Schrodinger, Seattle Genetics, Syros, Takeda, and Tolero. B.J. Druker potential competing interests-- SAB: Adela Bio, Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Celgene, DNA SEQ, Nemucore Medical Innovations, Novartis, RUNX1 Research Program, Vivid Biosciences (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, Enliven Therapeutics, Iterion Therapeutics, GRAIL, Recludix Pharma; Board of Directors & Stock: Amgen, Vincerx Pharma; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; Advisory Committee: Multicancer Early Detection Consortium; Founder: VB Therapeutics; Sponsored Research Agreement: Enliven Therapeutics, Recludix Pharma; Clinical Trial Funding: Novartis, Astra-Zeneca; Royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana-Farber Cancer Institute (one Merck exclusive license, one CytoImage, Inc. exclusive license, and one Sun Pharma Advanced Research Company non-exclusive license); US Patents 4326534, 6958335, 7416873, 7592142, 10473667, 10664967, 11049247. T.P. Braun has received research support from AstraZeneca, Blueprint Medicines as well as Gilead Sciences and is the institutional PI on the FRIDA trial sponsored by Oryzon Genomics. The authors certify that all compounds tested in this study were chosen without input from any of our industry partners. The other authors do not have competing interests, financial or otherwise.
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