RT Journal Article
SR Electronic
T1 A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.22.465184
DO 10.1101/2021.10.22.465184
A1 Yadira M. Soto-Feliciano
A1 Francisco J. Sánchez-Rivera
A1 Florian Perner
A1 Douglas W. Barrows
A1 Edward R. Kastenhuber
A1 Yu-Jui Ho
A1 Thomas Carroll
A1 Yijun Xiong
A1 Alexey Soshnev
A1 Leah Gates
A1 Mary Clare Beytagh
A1 David Cheon
A1 Shengqing Gu
A1 X. Shirley Liu
A1 Andrei V. Krivtsov
A1 Maximiliano Meneses
A1 Elisa de Stanchina
A1 Richard M. Stone
A1 Scott A. Armstrong
A1 Scott W. Lowe
A1 C. David Allis
YR 2021
UL http://biorxiv.org/content/early/2021/10/22/2021.10.22.465184.abstract
AB 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.