American Association for Cancer Research
cd-22-0416_supplementary_figures_suppsf1.pdf (28.5 MB)

Supplementary Figures from A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin–MLL Inhibition

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journal contribution
posted on 2023-04-04, 00:23 authored by Yadira M. Soto-Feliciano, Francisco J. Sánchez-Rivera, Florian Perner, Douglas W. Barrows, Edward R. Kastenhuber, Yu-Jui Ho, Thomas Carroll, Yijun Xiong, Disha Anand, Alexey A. Soshnev, Leah Gates, Mary Clare Beytagh, David Cheon, Shengqing Gu, X. Shirley Liu, Andrei V. Krivtsov, Maximiliano Meneses, Elisa de Stanchina, Richard M. Stone, Scott A. Armstrong, Scott W. Lowe, C. David Allis

Supplementary Figures S1-S25


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National Institute of General Medical Sciences (NIGMS)

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Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1–Menin and MLL3/4–UTX chromatin-modifying complexes that dictates response to Menin–MLL inhibitors. MLL1–Menin safeguards leukemia survival by impeding the binding of the MLL3/4–UTX complex at a subset of target gene promoters. Disrupting the Menin–MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1–Menin and MLL3/4–UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials. Menin–MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin–MLL inhibitor–resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses.This article is highlighted in the In This Issue feature, p. 1

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