ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
DOT1L Is a Novel Cancer Stem Cell Target for Triple-Negative Breast Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 2 of them syntheses that pooled it.
What it found
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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.
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Who cites it
52 citing papers in PubMed, 2 syntheses or guidelines pooled it, 67 citations in OpenAlex.
- Pooled it
- Evolution and hotspots in breast cancer organoid research: insights from a bibliometric and visual knowledge mapping study (2005-2024).Frontiers in oncology · 2025Pooled it
- Targeting DOT1L Reactivates HERV-K to Drive Cell-Autonomous and Paracrine Senescence in Adenocarcinoma of the Esophagogastric Junction.Cancer research · 2026Article
- Protein modification systems as cancer biomarkers and therapeutic targets.Precision clinical medicine · 2026Review
- Identification and Prognostic Analysis of Immune-Related Genes Co-Regulated by Key Histone Modifications in Breast Cancer.Current issues in molecular biology · 2026Article
- Dual function of DOT1L suppresses tumor cell-intrinsic immunogenicity in hepatocellular carcinoma.Oncogene · 2026Article
- Efficient Generation of Functional TCRαβbioRxiv : the preprint server for biology · 2026Article
- Harnessing PDX and PDX 2.0: the next-generation paradigm for precision oncology and translational breakthroughs.Molecular cancer · 2026Review
- DOT1L promotes immune evasion in lung adenocarcinoma through H3K79me2-mediated epigenetic activation of immune checkpoints.Frontiers in immunology · 2026Article
- CAV2-expressing nerves induce metabolic switch toward mitochondrial oxidative phosphorylation to promote cancer stemness.Nature communications · 2025Article
- Mechanisms of neuroendocrine differentiation in castration-resistant prostate cancer and advances in the treatment of neuroendocrine prostate cancer.Annals of medicine · 2025Review
- DOT1L inhibition exerts the anti-tumor effect by activating interferon signaling in breast cancer cells.Clinical epigenetics · 2025Article
- DOT1L as a Therapeutic Target: Insights into Epigenetic Regulation and Cancer Treatment.Biomolecules & therapeutics · 2025Review
- 5'-Methylthioadenosine Metabolic Reprogramming Drives H3K79 Monomethylation-Mediated PAK2 Upregulation to Promote Cadmium-Induced Breast Cancer Progression by Impairing Autophagic Flux.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Loss of BPTF restores estrogen response and suppresses metastasis of mammary tumors.Nature communications · 2025Article
- The latest progress of personalized drug screening and therapy research for common clinical tumors through the PDX model platform.Journal of pharmaceutical analysis · 2025Review
- Patient-derived xenograft models: Current status, challenges, and innovations in cancer research.Genes & diseases · 2025Review
- Epigenetic regulation of cancer stemness.Signal transduction and targeted therapy · 2025Review
- Discovery of the first-in-class DOT1L PROTAC degrader.European journal of medicinal chemistry · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeAlthough chemotherapies kill most cancer cells, stem cell-enriched survivors seed metastasis, particularly in triple-negative breast cancers (TNBC). TNBCs arise from and are enriched for tumor stem cells. Here, we tested if inhibition of DOT1L, an epigenetic regulator of normal tissue stem/progenitor populations, would target TNBC stem cells. EXPERIMENTAL
designEffects of DOT1L inhibition by EPZ-5676 on stem cell properties were tested in three TNBC lines and four patient-derived xenograft (PDX) models and in isolated cancer stem cell (CSC)-enriched ALDH1+ and ALDH1- populations. RNA sequencing compared DOT1L regulated pathways in ALDH1+ and ALDH1- cells. To test if EPZ-5676 decreases CSC in vivo, limiting dilution assays of EPZ-5676/vehicle pretreated ALDH1+ and ALDH1- cells were performed. Tumor latency, growth, and metastasis were evaluated. Antitumor activity was also tested in TNBC PDX and PDX-derived organoids.
resultsALDH1+ TNBC cells exhibit higher DOT1L and H3K79me2 than ALDH1-. DOT1L maintains MYC expression and self-renewal in ALDH1+ cells. Global profiling revealed that DOT1L governs oxidative phosphorylation, cMyc targets, DNA damage response, and WNT activation in ALDH1+ but not in ALDH1- cells. EPZ-5676 reduced tumorspheres and ALDH1+ cells in vitro and decreased tumor-initiating stem cells and metastasis in xenografts generated from ALDH1+ but not ALDH1- populations in vivo. EPZ-5676 significantly reduced growth in vivo of one of two TNBC PDX tested and decreased clonogenic 3D growth of two other PDX-derived organoid cultures.
conclusionsDOT1L emerges as a key CSC regulator in TNBC. Present data support further clinical investigation of DOT1L inhibitors to target stem cell-enriched TNBC.
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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.