An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element

• Main Authors: Mansour, M. R. (Author), Abraham, B. J. (Author), Anders, L. (Author), Berezovskaya, A. (Author), Gutierrez, A. (Author), Durbin, A. D. (Author), Etchin, J. (Author), Lawton, L. (Author), Sallan, S. E. (Author), Silverman, L. B. (Author), Loh, M. L. (Author), Hunger, S. P. (Author), Sanda, T. (Author), Look, A. T. (Author), Young, Richard A. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Whitehead Institute for Biomedical Research (Contributor), Young, Richard A (Contributor)
• Format: Article
• Language: English
• Published: American Association for the Advancement of Science (AAAS), 2017-01-12T19:27:14Z.
• Subjects: Article
• Online Access: Get fulltext

 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.