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

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

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 5

Gene expression compensation by MLL1/COMPASS in MLL3/4-KO cells.

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Gene expression compensation by MLL1/COMPASS in MLL3/4-KO cells. (A) MLL...
(A) MLL3/4 KO versus WT log2FC average plot showing the relative genomic binding of H3K4me3, MLL1, MLL2, Menin, and SET1A surrounding the TSS of genes that were significantly upregulated in MLL3/4-KO versus WT cells (selected based on Padj < 0.01 and logFC > 1, n = 1548). (B) The significantly downregulated genes in MLL3/4 KO v.s. WT were selected based on Padj < 0.01 and logFC < –1. The log2FC average plot showing the relative genomic binding of H3K4me3, MLL1, MLL2, Menin, and SET1A surrounding the TSS of genes that were significantly downregulated in MLL3/4 KO versus WT (selected based on Padj < 0.01 and logFC < –1, n = 1,377). (C) MLL1C (MLL1 Carboxyl-terminal antibody) ChIP-Seq peaks in both WT and MLL3/4-KO cells were merged and sorted. Average plot showing the MLL1C signal in WT and MLL3/4-KO cells centered on all MLL1 peaks. n = 11,687. (D) Venn diagram showing the overlap of MLL1C peaks found in WT and MLL3/4-KO cells. Approximately 82.9% of MLL1C peaks detected in MLL3/4-KO cells are de novo peaks. (E) Change in cell viability of WT and MLL3/4-KO cells in response to WDR5-0103 inhibitor treatment. n = 3 for each specific concentration in WT and MLL3/4 KO.