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Science. 2014 Dec 12;346(6215):1373-7. doi: 10.1126/science.1259037. Epub 2014 Nov 13.

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

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
2
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
4
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA.
5
Department of Pediatrics, Benioff Children's Hospital, University of California San Francisco, CA 94143, USA.
6
Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO 80045, USA.
7
Cancer Science Institute of Singapore, National University of Singapore, and Department of Medicine, Yong Loo Lin School of Medicine, 117599, Singapore.
8
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. thomas_look@dfci.harvard.edu young@wi.mit.edu.
9
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA. thomas_look@dfci.harvard.edu young@wi.mit.edu.

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.

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PMID:
25394790
PMCID:
PMC4720521
DOI:
10.1126/science.1259037
[Indexed for MEDLINE]
Free PMC Article

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