RT Journal Article
SR Electronic
T1 Dual Targeting of FLT3 and LSD1 Disrupts the MYC Super-Enhancer Complex in Acute Myeloid Leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.17.476469
DO 10.1101/2022.01.17.476469
A1 William Yashar
A1 Brittany M. Smith
A1 Daniel J. Coleman
A1 Jake VanCampen
A1 Garth Kong
A1 Jommel Macaraeg
A1 Joseph Estabrook
A1 Emek Demir
A1 Nicola Long
A1 Dan Bottomly
A1 Shannon K. McWeeney
A1 Jeffrey W. Tyner
A1 Brian J. Druker
A1 Julia E. Maxson
A1 Theodore P. Braun
YR 2022
UL http://biorxiv.org/content/early/2022/01/18/2022.01.17.476469.abstract
AB 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 demethylase 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. The drug combination 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 inhibition results in the suppression of MYC-bound promoters and the activation of PU.1-bound enhancers. Regulon enrichment analysis in primary AML samples nominated STAT5 as a putative regulator of MYC gene expression. Inhibition of FLT3 results in a loss of STAT5 binding at the MYC blood super-enhancer and a loss of super-enhancer activation. In contrast, LSD1 inhibition prevents the removal of repressive H3K9me1 marks at MYC target genes, resulting in suppression of MYC expression. We validated these findings in 66 primary AML samples including 17 FLT3-ITD-positive AML samples, with the 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 the FLT3 and LSD1 inhibitor combination 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 investigation of dual FLT3 and LSD1 inhibition in a clinical trial.Competing Interest StatementWMY potential competing interests -- 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., WMY surrendered all of his common stock options in 03/2021. JWT 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. JEM -- SAB: Ionis pharmaceuticals, Research Funding: Gilead Sciences. BJD potential competing interests -- SAB: Aileron Therapeutics, Therapy Architects (ALLCRON), Cepheid, Celgene, RUNX1 Research Program, Nemucore Medical Innovations, Novartis, Vivid Biosciences (inactive), Gilead Sciences (inactive); SAB & Stock: Aptose Biosciences, Blueprint Medicines, EnLiven Therapeutics, Iterion Therapeutics, GRAIL, Recludix Pharma; Scientific Founder: MolecularMD (inactive, acquired by ICON); Board of Directors & Stock: Amgen, Vincerx Pharma; Board of Directors: Burroughs Wellcome Fund, CureOne; Joint Steering Committee: Beat AML LLS; 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. 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.