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

Mansour, MR; Abraham, BJ; Anders, L; Berezovskaya, A; Gutierrez, A; Durbin, AD; Etchin, J; ... Look, AT; + view all (2014) An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science , 346 (6215) pp. 1373-1377. 10.1126/science.1259037. Green open access

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Abstract

In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that 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 its 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, which suggests 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.

Type: Article
Title: An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/science.1259037
Publisher version: https://doi.org/10.1126/science.1259037
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1456271
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