An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma Academic Article uri icon

Overview

MeSH Major

  • Carcinoma, Adenoid Cystic
  • Enhancer Elements, Genetic
  • Oncogene Proteins v-myb
  • Translocation, Genetic

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.

publication date

  • March 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4767593

Digital Object Identifier (DOI)

  • 10.1038/ng.3502

PubMed ID

  • 26829750

Additional Document Info

start page

  • 265

end page

  • 72

volume

  • 48

number

  • 3