An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma
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Author
Cotton, Matthew J.
Gillespie, Shawn M.
Ryan, Russell J.H.
Kluk, Michael J.
Carey, Christopher D.
Afrogheh, Amir H.
Queimado, Lurdes
Qi, Jun
Wick, Michael J.
El-Naggar, Adel K.
Moskaluk, Christopher A.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ng.3502Metadata
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Drier, 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.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 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767593/pdf/Terms of Use
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