A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia
Open accessAbstract
Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL.
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Genetic models have demonstrated that alteration of enhancer function can cause hematologic diseases.
“Genetic models have demonstrated that alteration of enhancer function can cause hematologic diseases49, 50.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [50]
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- Authors
- Herranz, D., Ambesi-Impiombato, A., Palomero, T., Schnell, S. A., Belver, L., Wendorff, A. A., Xu, L., Castillo-Martin, M., Llobet-Navás, D., Cordon-Cardo, C., Clappier, E., Soulier, J., & Ferrando, A. A.
- Affiliations
- Columbia University (US)
- Columbia University Irving Medical Center (US)
- Inserm (FR)
- Corresponding author
- Ferrando, Adolfo A
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-09-07
- Volume
- 20
- Issue
- 10
- Pages
- 1130-1137
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4192073
- OpenAlex
- W2091517552
- Cited by
- 405
- References
- 60
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 29 · 2023: 30 · 2022: 43 · 2021: 48 · 2020: 38 · 2019: 40 · 2018: 45 · 2017: 39 · 2016: 29 · 2015: 24 · 2014: 3
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-10-IBHU-0002)
- National Cancer Institute (P01CA087497, R01CA120196, CA120196)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Notch1, T-cell acute lymphoblastic leukemia, T cell development, chromosomal duplication, super-enhancers, long-range enhancers, T-cell transformation, therapeutic target
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Female, Gene Amplification, Humans, Male, Mice, Inbred C57BL, Oncogenes, T-Lymphocytes, Neoplastic Stem Cells, Genes, myc, Mice, Knockout, Jurkat Cells, Lymphopoiesis, Cell Line, Tumor, Mice, Receptor, Notch1, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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