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An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element
Open accessAbstract
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell’s transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase–binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells.
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“The ability of AlphaGenome to simultaneously score variant effects across all modalities accurately recapitulates the mechanisms of clinically relevant variants near the TAL1 oncogene6.”
From Advancing regulatory variant effect prediction with AlphaGenome (2026) · cites this paper as [6]
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“Detailed ALT–REF predictions for an oncogenic insertion (chr. 1: 47239296: C>ACG) characterized in ref. 6. Shown are differences between AlphaGenome predictions between the ALT and REF sequences of the variant in CD34+ CMP tracks. The ALT sequence increases expression of the TAL1 gene 7.5 kb away.”
From Advancing regulatory variant effect prediction with AlphaGenome (2026) · cites this paper as [6]
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“We evaluated three groups of gain-of-function mutations affecting the TAL1 gene in T cell acute lymphoblastic leukaemia (T-ALL): a cluster of 5′ neo-enhancer mutations upstream of the TAL1 TSS6,33, an intronic single-nucleotide variant (SNV)34 and a 3′ neo-enhancer35.”
From Advancing regulatory variant effect prediction with AlphaGenome (2026) · cites this paper as [6]
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“By contrast, the alternative sequence introduced a MYB motif at the variant position predicted to increase TAL1 expression, chromatin accessibility and H3K27ac chromatin marks (Fig. 6e), as discovered previously6.”
From Advancing regulatory variant effect prediction with AlphaGenome (2026) · cites this paper as [6]
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Metadata
- Authors
- Mansour, M. R., Abraham, B. J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A. D., Etchin, J., Lawton, L., Sallan, S. E., Silverman, L. B., Loh, M. L., Hunger, S. P., Sanda, T., Young, R. A., & Look, A. T.
- Affiliations
- Harvard University (US)
- Whitehead Institute for Biomedical Research (US)
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
- Boston Children's Hospital (US)
- University of California, San Francisco (US)
- Children's Hospital Colorado (US)
- National University of Singapore (SG)
- Corresponding author
- Abraham, Brian J.
- Anders, Lars
- Young, Richard A.
- Look, A. Thomas
- ORCID
- Venue
- Science
- Published
- 2014-12-12
- Volume
- 346
- Issue
- 6215
- Pages
- 1373-1377
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4720521
- OpenAlex
- W2082414039
- Cited by
- 801
- References
- 46
- Citations by year
- 2026: 32 · 2025: 49 · 2024: 61 · 2023: 77 · 2022: 84 · 2021: 85 · 2020: 80 · 2019: 62 · 2018: 65 · 2017: 77 · 2016: 76 · 2015: 49 · 2014: 4
- FWCI
- 28.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- UCL Discovery (University College London) (submittedVersion)
- PMC
- Funders
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (R21CA167124, CA114766, CA30969, R01CA176746, CA‐98413, U10CA098413, U24CA114766, U10CA030969, P01CA068484, CA 29139, R01CA120215, 5P01CA68484, U10CA029139, U10CA098543, P01CA109901, CA167124, CA120215, CA-98543, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Keywords
- super-enhancers, T-cell acute lymphoblastic leukemia, MYB transcription factors, somatic mutations, H3K27 acetylation, CBP, RUNX1, GATA3, transcriptional regulation, oncogene expression
- MeSH terms
- T-Cell Acute Lymphocytic Leukemia Protein 1, Acetylation, Base Sequence, Binding Sites, Enhancer Elements, Genetic, Histones, Humans, Molecular Sequence Data, Mutation, Oncogenes, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myb, DNA, Intergenic, Cell Line, Tumor, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, INDEL Mutation, Protein Interaction Domains and Motifs
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