Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Drier, Y, Cotton, MJ, Williamson, KE, Gillespie, SM, Ryan, RJH, 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, BE |
Journal | Nat Genet |
Volume | 48 |
Issue | 3 |
Pages | 265-72 |
Date Published | 2016 Mar |
ISSN | 1546-1718 |
Keywords | Carcinoma, Adenoid Cystic, Cell Line, Tumor, Cell Lineage, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Humans, Oncogene Proteins v-myb, Oncogene Proteins, Fusion, Transcription Factors, Translocation, Genetic, Tumor Suppressor Proteins |
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. |
URL | http://dx.doi.org/10.1038/ng.3502 |
DOI | 10.1038/ng.3502 |
Pubmed | |
Alternate Journal | Nat. Genet. |
PubMed ID | 26829750 |
PubMed Central ID | PMC4767593 |
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 |