Unveiling the Role of MLL3 and MLL4 Mutations in Cancer: A CRISPR Study Revealing Targeted Metabolic Dependency

2023-06-30 04:05:14

Mutations in a set of genes known as the Set1-Associated Protein Complex (COMPASS) family, specifically mutations in the MLL3 and MLL4 genes, are common in patients with many types of cancer.

To better understand these genes and what role they play in tumor growth, researchers from the Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, USA conducted a CRISPR in embryonic stem cells from mice with MLL3 and MLL4 knockouts. According to the study, cells with both MLL3 and MLL4 deleted appeared to increase the production of purine, an essential component of DNA and RNA.

To see if they might be stopped with a similar tactic, the researchers tested their method on cells from colorectal cancer patients. According to the study, they found that cells with mutations were more sensitive to the purine synthesis inhibitor than those expressing wild-type MLL4.

CRISPR screening in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality following suppression of the purine and pyrimidine nucleotide synthesis pathways. Consistently, a shift in metabolic activity towards increased purine synthesis was observed in MLL3/4 knockout (KO) mESCs. These cells also showed increased sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature.

RNA sequencing identified the major MLL3/4 target genes consistent with suppression of purine metabolism, and tandem mass tag (TMT) proteomic profiling further confirmed the upregulation of purine synthesis in cells. MLL3/4 KO. Mechanically, the compensation for MLL1/COMPASS underlay these effects.

Finally, tumors with mutations in MLL3 and/or MLL4 were shown to be highly sensitive to lometrexol in vivo, both in culture and in animal models of cancer. The results describe a targeted metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy of cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.

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The team hopes to move on to preclinical studies to further validate the efficacy of the approach.

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