A molecular switch between mammalian MLL complexes dictates response to menin-MLL inhibition Journal Article

   

Authors:	Soto-Feliciano, Y. M.; Sánchez-Rivera, F. J.; Perner, F.; Barrows, D. W.; Kastenhuber, E. R.; Ho, Y. J.; Carroll, T.; Xiong, Y.; Anand, D.; Soshnev, A. A.; Gates, L.; Beytagh, M. C.; Cheon, D.; Gu, S.; Liu, X. S.; Krivtsov, A. V.; Meneses, M.; de Stanchina, E.; Stone, R. M.; Armstrong, S. A.; Lowe, S. W.; Allis, C. D.
Article Title:	A molecular switch between mammalian MLL complexes dictates response to menin-MLL inhibition
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. SIGNIFICANCE: 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. ©2022 The Authors; Published by the American Association for Cancer Research.
Keywords:	leukemia; genetics; mouse; animal; metabolism; animals; mice; transcription factor; cell line, tumor; transcription factors; chromatin; histone-lysine n-methyltransferase; mammal; tumor cell line; mammals; histone lysine methyltransferase; mixed lineage leukemia protein; myeloid-lymphoid leukemia protein; humans; human
Journal Title:	Cancer Discovery
Volume:	13
Issue:	1
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2023-01-01
Start Page:	146
End Page:	169
Language:	English
DOI:	10.1158/2159-8290.Cd-22-0416
PUBMED:	36264143
PROVIDER:	scopus
PMCID:	PMC9827117
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85145955276&doi=10.1158%2f2159-8290.CD-22-0416&partnerID=40&md5=52318430b0f2cdd6fc385c68edb7ff56
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Scott W. Lowe -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/202516