An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.
An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.
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DOI：
10.1038/ng.3502
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发表时间：
2016-03
期刊：
影响因子：
30.8
通讯作者：
Bernstein BE
中科院分区：
文献类型：
--
作者：
Drier Y;Cotton MJ;Williamson KE;Gillespie SM;Ryan RJ;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
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.
