An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element
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 lymphob...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/106462 https://orcid.org/0000-0001-8855-8647 |
| _version_ | 1811087379980615680 |
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| author | 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. Look, A. T. Young, Richard A. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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. Look, A. T. Young, Richard A. |
| author_sort | Mansour, M. R. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:45:10Z |
| format | Article |
| id | mit-1721.1/106462 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:45:10Z |
| publishDate | 2017 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1064622022-09-28T15:55:14Z An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element 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. Look, A. T. Young, Richard A. Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Young, Richard 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. National Institutes of Health (U.S.) (Grants CA98543, CA114766, CA98413, CA30969 and CA29139) 2017-01-12T19:27:14Z 2017-01-12T19:27:14Z 2014-11 2014-07 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/106462 Mansour, M. R. et al. “An Oncogenic Super-Enhancer Formed through Somatic Mutation of a Noncoding Intergenic Element.” Science 346.6215 (2014): 1373–1377. https://orcid.org/0000-0001-8855-8647 en_US http://dx.doi.org/10.1126/science.1259037 Science Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | 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. Look, A. T. Young, Richard A. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element |
| title | An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element |
| title_full | An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element |
| title_fullStr | An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element |
| title_full_unstemmed | An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element |
| title_short | An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element |
| title_sort | oncogenic super enhancer formed through somatic mutation of a noncoding intergenic element |
| url | http://hdl.handle.net/1721.1/106462 https://orcid.org/0000-0001-8855-8647 |
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