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

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.

Understanding the role of the MYB oncogene in human breast cancer: targets and functions

“…Moreover, RAD51C is a MYB-regulated gene (Quintana et al, 2011, Drier et al, 2016. My data in Figures 4.9 and 4.10 show that silencing MYB in the MYB shRNA cells did not detectably change the total amount of RAD51 or cytosolic RAD51 expression, but reduced nuclear RAD51 expression after exposure to +Dox+ETO treatment.…”

“…Previous studies indicated that several genes (BRCA1, CEP164 and TOPBP1) that were involved in DNA repair were MYB target genes (Quintana et al, 2011, Drier et al, 2016. Furthermore, both BRCA1 (Cousineau et al, 2005) and TOPBP1 (Moudry et al, 2016) regulate RAD51 function in response to DNA damage.…”

“…Thus, using the broader criteria, 27 potential and known target genes were validated by Q-PCR (also see Discussion). b The capital letter Y in the ChIP column indicates MYB binding sites were identified in one of three published ChIP datasets (Quintana et al, 2011, Drier et al, 2016; N indicates no MYB binding site was identified in these datasets. represents MYB target genes in the MYB shRNA+Dox group showed significant differential expression (P<0.05) when only compared to the NS+Dox group; Panel (c) represents MYB target genes in the MYB shRNA+Dox group that showed no significant differential expression (P>0.05) when compared to the MYB shRNA-Dox and the NS+Dox groups.…”

“…The human MYB locus has been mapped to a region (6q21-23) of chromosome 6 that is involved in chromosomal translocations in both myeloid and lymphoid neoplasms (Harper et al, 1983). These chromosomal translocations commonly lead to MYB overexpression in myeloid and lymphoid neoplasms and adenoid cystic carcinomas (Harper et al, 1983, Pelicci et al, 1984, West et al, 2011, Drier et al, 2016. The MYB gene family contains another two members, namely, MYBL1 (also known as A-MYB) and MYBL2 (also known as B-MYB) which have different roles in various tissues (Nomura et al, 1988).…”

“…The 193 differentially-expressed genes that were in common between the two different MYB shRNAs was also integrated with a published ChIP-Seq dataset from adenoid cystic carcinoma (ACC) (Drier et al, 2016) to identify direct MYB target genes that are directly regulated by MYB bound within the gene. These published ChIP datasets were generated by using three different anti-MYB antibodies to identify genomic MYB binding sites in a gene because of known problems with MYB antibody specificity/effectiveness in ChIP studies ( Figure 3.11(c)).…”