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Nat Genet DOI:10.1038/ng.3502

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

Publication TypeJournal Article
Year of Publication2016
AuthorsDrier, 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
JournalNat Genet
Volume48
Issue3
Pages265-72
Date Published2016 Mar
ISSN1546-1718
KeywordsCarcinoma, 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.

URLhttp://dx.doi.org/10.1038/ng.3502
DOI10.1038/ng.3502
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26829750?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID26829750
PubMed Central IDPMC4767593
Grant ListHHSN268200900039C / 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