An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element
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Author(s)
Mansour, M. R.
Abraham, Brian Joseph
Anders, L.
Berezovskaya, A.
Gutierrez, A.
Durbin, A. D.
Etchin, J.
Lawton, L.
Sallan, S. E.
Silverman, L. B.
Date Issued
November 2014
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Mansour, M. R. et al. “An Oncogenic Super-Enhancer Formed through Somatic Mutation of a Noncoding Intergenic Element.” Science 346.6215 (2014): 1373–1377.
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Author's final manuscript
Abstract
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, which 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 it’s 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, suggesting 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1126/science.1259037
