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

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, 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 lymp...

Full description

Saved in:
Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2014-12, Vol.346 (6215), p.1373-1377
Main Authors: Mansour, Marc R., Abraham, Brian J., Anders, Lars, Berezovskaya, Alla, Gutierrez, Alejandro, Durbin, Adam D., Etchin, Julia, Lawton, Lee, Sallan, Stephen E., Silverman, Lewis B., Loh, Mignon L., Hunger, Stephen P., Sanda, Takaomi, Young, Richard A., Look, A. Thomas
Format: Article
Language:eng
Subjects:
Acute T cell leukemia
Alleles
Binding
Binding sites
Cancer
Cell lines
Coding
Fetal stem cells
Gene expression
Genes
Genetic loci
Genetic mutation
Genomics
Government regulations
Histones
Leukemias
Mutation
Mutations
Oncogenes
T lymphocytes
Upstream
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0036-8075
1095-9203