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Nat Genet. 2016 Mar;48(3):265-72. doi: 10.1038/ng.3502. Epub 2016 Feb 1.

An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.

Author information

1
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
3
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
5
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
8
South Texas Accelerated Research Therapeutics (START), San Antonio, Texas, USA.
9
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
10
Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.
11
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
12
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Abstract

Translocation events are frequent in cancer and may create chimeric fusions or 'regulatory rearrangements' that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps highlight distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter. Remarkably, MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Bromodomain inhibitors slow tumor growth in ACC primagraft models in vivo. Thus, our study identifies super-enhancer translocations that drive MYB expression and provides insight into downstream MYB functions in alternate ACC lineages.

PMID:
26829750
PMCID:
PMC4767593
DOI:
10.1038/ng.3502
[Indexed for MEDLINE]
Free PMC Article

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