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

Yotam Drier, Matthew J. Cotton, Kaylyn E. Williamson, Shawn M. Gillespie, Russell J.H. Ryan, Michael J. Kluk, Christopher D. Carey, Scott J. Rodig, Lynette M. Sholl, Amir H. Afrogheh, William C. Faquin, Lurdes Queimado, Jun Qi, Michael J. Wick, Adel K. El-Naggar, James E. Bradner, Christopher A. Moskaluk, Jon C. Aster, Birgit Knoechel*, Bradley E. Bernstein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

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.

Original languageAmerican English
Pages (from-to)265-272
Number of pages8
JournalNature Genetics
Volume48
Issue number3
DOIs
StatePublished - 1 Mar 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016 Nature America, Inc.

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