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

Yotam Drier; Matthew J. Cotton; Kaylyn E. Williamson; Shawn M. Gillespie; Russell J.H. Ryan; Michael J. Kluk; Christopher D. Carey; Scott J. Rodig; Lynette M. Sholl; Amir H. Afrogheh; William C. Faquin; Lurdes Queimado; Jun Qi; Michael J. Wick; Adel K. El-Naggar; James E. Bradner; Christopher A. Moskaluk; Jon C. Aster; Birgit Knoechel; Bradley E. Bernstein

doi:10.1038/ng.3502

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

Yotam Drier, Matthew J. Cotton, Kaylyn E. Williamson, Shawn M. Gillespie, Russell J.H. Ryan, Michael J. Kluk, Christopher D. Carey, Scott J. Rodig, Lynette M. Sholl, Amir H. Afrogheh, William C. Faquin, Lurdes Queimado, Jun Qi, Michael J. Wick, Adel K. El-Naggar, James E. Bradner, Christopher A. Moskaluk, Jon C. Aster, Birgit Knoechel^*, Bradley E. Bernstein

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

211 Scopus citations

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.

Original language	English
Pages (from-to)	265-272
Number of pages	8
Journal	Nature Genetics
Volume	48
Issue number	3
DOIs	https://doi.org/10.1038/ng.3502
State	Published - 1 Mar 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 Nature America, Inc.

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Drier, Y., Cotton, M. J., Williamson, K. E., Gillespie, S. M., Ryan, R. J. H., Kluk, M. J., Carey, C. D., Rodig, S. J., Sholl, L. M., Afrogheh, A. H., Faquin, W. C., Queimado, L., Qi, J., Wick, M. J., El-Naggar, A. K., Bradner, J. E., Moskaluk, C. A., Aster, J. C., Knoechel, B., & Bernstein, B. E. (2016). An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nature Genetics, 48(3), 265-272. https://doi.org/10.1038/ng.3502

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title = "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 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.",

author = "Yotam Drier and Cotton, {Matthew J.} and Williamson, {Kaylyn E.} and Gillespie, {Shawn M.} and Ryan, {Russell J.H.} and Kluk, {Michael J.} and Carey, {Christopher D.} and Rodig, {Scott J.} and Sholl, {Lynette M.} and Afrogheh, {Amir H.} and Faquin, {William C.} and Lurdes Queimado and Jun Qi and Wick, {Michael J.} and El-Naggar, {Adel K.} and Bradner, {James E.} and Moskaluk, {Christopher A.} and Aster, {Jon C.} and Birgit Knoechel and Bernstein, {Bradley E.}",

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doi = "10.1038/ng.3502",

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Drier, Y, Cotton, MJ, Williamson, KE, Gillespie, SM, Ryan, RJH, 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 2016, 'An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma', Nature Genetics, vol. 48, no. 3, pp. 265-272. https://doi.org/10.1038/ng.3502

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AU - Wick, Michael J.

AU - El-Naggar, Adel K.

AU - Bradner, James E.

AU - Moskaluk, Christopher A.

AU - Aster, Jon C.

AU - Knoechel, Birgit

AU - Bernstein, Bradley E.

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AB - 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.

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

Abstract

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