Drier et al. describe how enhancer hijacking rewires the regulation of the oncogenic transcription factor MYB and drives adenoid cystic carcinoma. Translocation of MYB near super-enhancers that are themselves bound by MYB creates a vicious cycle where MYB drives its own transcription. 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. Additional genetic hits to the Notch pathway activate Notch signaling and shift the epigenetic balance between myoepithelial and luminal cells to luminal only high grade ACC. Bromodomain inhibitors that block enhancer function slow tumor growth of low-grade ACC xenografts models in vivo.
Key findings:
- MYB rearrangements often retain intact MYB transcript, translocating it to the NFIB locus or other loci rich in strong enhancers.
- The translocated enhancers are driven by MYB binding, yielding oncogenic positive feedback loop driving very high levels of MYB.
- MYB overexpression support tumorgenicity of both myoepithelial cells and luminal cells in adenoid cystic carcinoma, where MYB cooperates with TP63 in myoepithelial cells and support Notch signaling in luminal cells.
- Genetic hits to the Notch pathways shift the epigenetic balance toward luminal cells only, yielding high-grade aggressive adenoid cystic carcinoma.
- The bromodomain inhibitor JQ1, known to block enhancer function and specifically super-enhancer function inhibit growth of lower grade adenoid cystic carcinoma in mice xenografts.
An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma
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. Nature Genetics 2016 Mar;48(3):265-72.