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Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations
Zibo Zhao, … , Issam Ben-Sahra, Ali Shilatifard
Zibo Zhao, … , Issam Ben-Sahra, Ali Shilatifard
Published May 30, 2023
Citation Information: J Clin Invest. 2023;133(13):e169993. https://doi.org/10.1172/JCI169993.
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Research Article Genetics Metabolism Article has an altmetric score of 25

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

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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.

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

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Figure 8

The roadmap of molecular changes and cellular phenotypes when cells lose MLL3/4-COMPASS.

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The roadmap of molecular changes and cellular phenotypes when cells lose...
To identify targetable cellular vulnerabilities that arise when MLL3/4 are compromised, a variety of multiomics approaches were utilized including a synthetic lethality screen and metabolic, transcriptomic, and proteomic profiling. In addition to the downregulation of MLL3/4 target genes, the loss of MLL3/4 also leads to the activation of MLL1/COMPASS, which drives the upregulated expression of de novo purine metabolism genes. This upregulation was found to be reversible by the specific inhibition of interaction between MLL1 and the cofactor WDR5. These findings led to the therapeutic evaluation of the de novo purine nucleotide synthesis pathway targeting in MLL4 mutant colorectal cancer using lometrexol, a specific inhibitor of the purine synthesis enzyme GART. This promising approach may offer new hope for patients with MLL4 mutant colorectal cancer.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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