An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.
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| 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. |
| Year of Publication | 2016
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| Journal | Nat Genet
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| Volume | 48
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| Issue | 3
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| Pages | 265-72
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| Date Published | 2016 Mar
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| ISSN | 1546-1718
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| URL | |
| DOI | 10.1038/ng.3502
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| PubMed ID | 26829750
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| PubMed Central ID | PMC4767593
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| Grant list | HHSN268200900039C / DE / NIDCR NIH HHS / United States
U54 HG006991 / HG / NHGRI NIH HHS / United States
HHSN268200900039C 04 / PHS HHS / United States
Howard Hughes Medical Institute / United States
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