TY - JOUR T1 - A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition JF - bioRxiv DO - 10.1101/2021.10.22.465184 SP - 2021.10.22.465184 AU - Yadira M. Soto-Feliciano AU - Francisco J. Sánchez-Rivera AU - Florian Perner AU - Douglas W. Barrows AU - Edward R. Kastenhuber AU - Yu-Jui Ho AU - Thomas Carroll AU - Yijun Xiong AU - Alexey Soshnev AU - Leah Gates AU - Mary Clare Beytagh AU - David Cheon AU - Shengqing Gu AU - X. Shirley Liu AU - Andrei V. Krivtsov AU - Maximiliano Meneses AU - Elisa de Stanchina AU - Richard M. Stone AU - Scott A. Armstrong AU - Scott W. Lowe AU - C. David Allis Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/22/2021.10.22.465184.abstract N2 - The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1- rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.Competing Interest StatementC.D.A. is a co-founder of Chroma Therapeutics and Constellation Pharmaceuticals and a Scientific Advisory Board member of EpiCypher. S.W.L. is an advisor for and has equity in the following biotechnology companies: ORIC Pharmaceuticals, Faeth Therapeutics, Blueprint Medicines, Geras Bio, Mirimus Inc., and PMV Pharmaceuticals. S.W.L. also acknowledges receiving funding and research support from Agilent Technologies for the purposes of massively parallel oligo synthesis. S.A.A. has been a consultant and/or shareholder for Vitae/Allergan Pharmaceuticals, Epizyme Inc., Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Syros Pharmaceuticals, OxStem Oncology, Accent Therapeutics, and Mana Therapeutics. S.A.A. has received research support from Janssen, Novartis, and AstraZeneca. The remaining authors declare no competing interests. ER -