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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 6

MLL4 mutant colorectal cancer cells are selectively sensitive to LTX treatment.

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MLL4 mutant colorectal cancer cells are selectively sensitive to LTX tre...
(A) Cells were treated with 0–30 μM LTX with 3-fold dilution for 72 hours. A CellTiter-Glo luminescent cell viability assay was performed to determine the percentage of inhibition under these conditions. The line plot compares the sensitivity of all cell lines tested. n = 3 for each specific concentration in each cell line. (B) Cells were treated with DMSO or 1 μM LTX for 24 hours and whole cell lysates were used for Western blot against cell cycle (H3 Ser10-p, CDT1, CyclinB1, Geminin, CyclinE1, CyclinA2, and p-cdc2) and apoptosis (PARP and Caspase3) markers using Hsp90 and β-tubulin as loading controls. (C) Venn diagram showing the overlap of genes downregulated by LTX treatment versus control in RKO, HCT116, and DLD1 cells. (D) Hierarchical clustering heatmap showing the genes with expression downregulated by LTX treatment versus control in common among RKO, HCT116, and DLD1 cells (n = 885). (E) Box plot showing the logFC of the 885 downregulated genes in common among RKO, HCT116, and DLD1 cells upon LTX treatment. An unpaired t test was used to calculate the P value. Gene expression was significantly different in all the MLL4 mutant cell lines compared with MLL4 WT cells. (F) A network was constructed from a subset of representative cluster terms. Each term is represented by a circular node, where node size is proportional to the number of input genes falling under that term, and where color represents cluster identity. Terms with a similarity score > 0.3 are linked by an edge (for which thickness represents the similarity score). The network was visualized using Cytoscape with “force-directed” layout and with edges bundled for clarity. One representative term from each cluster was selected to be labeled with its term description.

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

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