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