An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element
Author(s)
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.; ... Show more Show less
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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.
Date issued
2014-11Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical ResearchJournal
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.
Version: Author's final manuscript
ISSN
0036-8075
1095-9203