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Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations

Authors :
Zibo Zhao
Kaixiang Cao
Jun Watanabe
Cassandra N. Philips
Jacob M. Zeidner
Yukitomo Ishi
Qixuan Wang
Sarah R. Gold
Katherine Junkins
Elizabeth T. Bartom
Feng Yue
Navdeep S. Chandel
Rintaro Hashizume
Issam Ben-Sahra
Ali Shilatifard
Source :
The Journal of Clinical Investigation, Vol 133, Iss 13 (2023)
Publication Year :
2023
Publisher :
American Society for Clinical Investigation, 2023.

Abstract

Epigenetic status–altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity toward increased purine synthesis in MLL3/4-KO mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA-Seq identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4-KO cells. Mechanistically, we demonstrated that compensation by MLL1/COMPASS was underlying these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vitro and in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.

Subjects

Subjects :
Genetics
Metabolism
Medicine

Details

Language :
English
ISSN :
15588238
Volume :
133
Issue :
13
Database :
Directory of Open Access Journals
Journal :
The Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsdoj.61972a1e2ad403ba273c50469a57ab6
Document Type :
article
Full Text :
https://doi.org/10.1172/JCI169993