ArticleThe Journal of clinical investigation2023
Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- Mapping of the hSOX10 Proximal Protein Interactome in Human Melanoma.Journal of proteome research · 2026Article
- Enhancer and metabolic rewiring by KMT2C-COMPASS or KMT2D-COMPASS family loss in cancer creates druggable vulnerabilities.Nature reviews. Cancer · 2026Review
- MLL3/4 methyltransferases regulate the differentiation of pluripotent stem cells through coordinating glycolysis and mitochondrial respiration.bioRxiv : the preprint server for biology · 2026Article
- Metabolic-Epigenetic Crosstalk in Takayasu Arteritis: The ANK2-MAVS-IL-8 Axis as a Novel Therapeutic Paradigm.International journal of molecular sciences · 2026Review
- A tryptophan-phenylalanine binding motif for the histone methyltransferases MLL4 and MLL3.The Journal of biological chemistry · 2026Article
- Histone lysine demethylases in breast cancer: molecular mechanisms, biological functions, and therapeutic intervention.Molecular cancer · 2025Review
- Histone methyltransferase PRDM9 promotes survival of drug-tolerant persister cells in glioblastoma.Nature communications · 2025Article
- In vivo gene editing of human hematopoietic stem and progenitor cells using envelope-engineered virus-like particles.Nature biotechnology · 2025Article
- Mapping of the hSOX10 protein interactome in human melanoma.bioRxiv : the preprint server for biology · 2025Article
- Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma.Cell death & disease · 2025Article
- Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies.Cell death discovery · 2025Review
- Epigenetic therapies targeting histone lysine methylation: complex mechanisms and clinical challenges.The Journal of clinical investigation · 2024Review
- Somatic mutations of MLL4/COMPASS induce cytoplasmic localization providing molecular insight into cancer prognosis and treatment.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 1 institution in 1 country.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.