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106462 |
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|a Mansour, M. R.
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|a Massachusetts Institute of Technology. Department of Biology
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|a Whitehead Institute for Biomedical Research
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|a Young, Richard A
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|a Abraham, B. J.
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|a Anders, L.
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|a Berezovskaya, A.
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|a Gutierrez, A.
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|a Durbin, A. D.
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|a Etchin, J.
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|a Lawton, L.
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|a Sallan, S. E.
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|a Silverman, L. B.
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|a Loh, M. L.
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|a Hunger, S. P.
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|a Sanda, T.
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|a Look, A. T.
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|a Young, Richard A.
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|a An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element
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|b American Association for the Advancement of Science (AAAS),
|c 2017-01-12T19:27:14Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/106462
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|a 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.
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|a National Institutes of Health (U.S.) (Grants CA98543, CA114766, CA98413, CA30969 and CA29139)
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|a en_US
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|a Article
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|t Science
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