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.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Drier Y,Cotton MJ,Williamson KE,Gillespie SM,Ryan RJ,Kluk MJ,Carey CD,Rodig SJ,Sholl LM,Afrogheh AH,Faquin WC,Queimado L,Qi J,Wick MJ,El-Naggar AK,Bradner JE,Moskaluk CA,Aster JC,Knoechel B,Bernstein BEdoi
10.1038/ng.3502subject
Has Abstractpub_date
2016-03-01 00:00:00pages
265-72issue
3eissn
1061-4036issn
1546-1718pii
ng.3502journal_volume
48pub_type
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