A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition

Authors

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

Publication Date

1-9-2023

Journal

Cancer Discovery

Abstract

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.

Keywords

Humans, Mice, Animals, Myeloid-Lymphoid Leukemia Protein, Histone-Lysine N-Methyltransferase, Cell Line, Tumor, Transcription Factors, Leukemia, Chromatin, Mammals

Comments

Supplementary Materials

PMID: 36264143