ArticleProceedings of the National Academy of Sciences of the United States of America2014
Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers.
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Who cites it
123 citing papers in PubMed, 172 citations in OpenAlex.
- OLIVE provides rapid visualization and analysis of chromatin tracing experiments.Cell reports methods · 2025Article
- The ESCRT protein CHMP5 promotes T cell leukemia by enabling BRD4-p300-dependent transcription.Nature communications · 2025Article
- Native stem cell transcriptional circuits define cardinal features of high-risk leukemia.The Journal of experimental medicine · 2025Article
- Probing the limits of cis-acting gene regulation using a model of allelic imbalance quantitative trait loci.PLoS genetics · 2025Article
- CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression.Cancer research · 2024Article
- Notch1 Phase Separation Coupled Percolation facilitates target gene expression and enhancer looping.Scientific reports · 2024Article
- Oncogenic Enhancers in Leukemia.Blood cancer discovery · 2024Review
- The cellular Notch1 protein promotes KSHV reactivation in an Rta-dependent manner.Journal of virology · 2024Article
- Oncogenic transcription factors instruct promoter-enhancer hubs in individual triple negative breast cancer cells.Science advances · 2024Article
- Notch1 Phase Separation Coupled Percolation facilitates target gene expression and enhancer looping.bioRxiv : the preprint server for biology · 2024Article
- Article
- Comprehensive genomic features indicative for Notch responsiveness.Nucleic acids research · 2024Article
- Identification of a Notch transcriptomic signature for breast cancer.Breast cancer research : BCR · 2024Article
- Spatial promoter-enhancer hubs in cancer: organization, regulation, and function.Trends in cancer · 2023Review
- DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance.Blood · 2023Article
- Review
- RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia.iScience · 2023Article
- Oncogenic signaling-mediated regulation of chromatin during tumorigenesis.Cancer metastasis reviews · 2023Review
- Notch Partners in the Long Journey of T-ALL Pathogenesis.International journal of molecular sciences · 2023Review
- A Therapeutically Targetable NOTCH1-SIRT1-KAT7 Axis in T-cell Leukemia.Blood cancer discovery · 2023Article
63 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 8 institutions in 4 countries.
Funding
Abstract
Notch is needed for T-cell development and is a common oncogenic driver in T-cell acute lymphoblastic leukemia. The protooncogene c-Myc (Myc) is a critical target of Notch in normal and malignant pre-T cells, but how Notch regulates Myc is unknown. Here, we identify a distal enhancer located >1 Mb 3' of human and murine Myc that binds Notch transcription complexes and physically interacts with the Myc proximal promoter. The Notch1 binding element in this region activates reporter genes in a Notch-dependent, cell-context-specific fashion that requires a conserved Notch complex binding site. Acute changes in Notch activation produce rapid changes in H3K27 acetylation across the entire enhancer (a region spanning >600 kb) that correlate with Myc expression. This broad Notch-influenced region comprises an enhancer region containing multiple domains, recognizable as discrete H3K27 acetylation peaks. Leukemia cells selected for resistance to Notch inhibitors express Myc despite epigenetic silencing of enhancer domains near the Notch transcription complex binding sites. Notch-independent expression of Myc in resistant cells is highly sensitive to inhibitors of bromodomain containing 4 (Brd4), a change in drug sensitivity that is accompanied by preferential association of the Myc promoter with more 3' enhancer domains that are strongly dependent on Brd4 for function. These findings indicate that altered long-range enhancer activity can mediate resistance to targeted therapies and provide a mechanistic rationale for combined targeting of Notch and Brd4 in leukemia.
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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.