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

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Science  12 Dec 2014:
Vol. 346, Issue 6215, pp. 1373-1377
DOI: 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.

A super-enhancer in leukemia development

Human cancer genome projects have provided a wealth of information about mutations that reside within the coding regions of genes and drive tumor growth by functionally altering protein products. However, this mutational portrait of cancer is incomplete: A growing number of mutations are being found within gene regulatory regions. Mansour et al. present an intriguing example of this in a study of a childhood cancer, T-cell acute lymphoblastic leukemia (see the Perspective by Vähärautio and Taipale). An oncogene known to drive the growth of this cancer is expressed at high levels in the leukemic cells because the cells harbor mutations that create a powerful superenhancer (a DNA sequence that activates transcription) upstream of the oncogene.

Science, this issue p. 1373; see also p. 1291

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