Drier, YotamCotton, Matthew J.Williamson, KaylynGillespie, Shawn M.Ryan, Russell J.H.Kluk, Michael J.Carey, Christopher D.Rodig, ScottSholl, LynetteAfrogheh, Amir H.Faquin, WilliamQueimado, LurdesQi, JunWick, Michael J.El-Naggar, Adel K.Bradner, James EMoskaluk, Christopher A.Aster, JonKnoechel, BirgitBernstein, Bradley2016-10-112016Drier, Y., M. J. Cotton, K. E. Williamson, S. M. Gillespie, R. J. Ryan, M. J. Kluk, C. D. Carey, et al. 2016. “An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.” Nature genetics 48 (3): 265-272. doi:10.1038/ng.3502. http://dx.doi.org/10.1038/ng.3502.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002632Translocation 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 reveal 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 the alternate ACC lineages.en-USJournal Article2016-10-1110.1038/ng.3502