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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We thank M. Rivera, N. Riggi, S. Puram, P. van Galen, J. Lohr and J. Kaufman for helpful discussions and critical comments on the manuscript; J. Voisine, R. Isenhart, R. Issner, H. Whitton, A. Spooner, M. Uziel, C. Epstein and N. Shoresh for technical assistance; T. Chan and V. Makarov for help with whole-genome sequencing data access; and the Salivary Gland Tumor Biorepository for providing the primary tumors (National Institute of Dental and Craniofacial Research (NIDCR) award reference HHSN268200900039C 04). This work was supported by the Adenoid Cystic Carcinoma Research Foundation (B.E.B. and B.K.), the Temares Family Foundation and the Howard Hughes Medical Institute. B.E.B. is an American Cancer Society Research Professor.

Author information

Author notes

    • Birgit Knoechel
    •  & Bradley E Bernstein

    These authors contributed equally to this work.


  1. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Yotam Drier
    • , Matthew J Cotton
    • , Kaylyn E Williamson
    • , Shawn M Gillespie
    • , Russell J H Ryan
    • , Amir H Afrogheh
    • , William C Faquin
    • , Birgit Knoechel
    •  & Bradley E Bernstein
  2. Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Yotam Drier
    • , Matthew J Cotton
    • , Kaylyn E Williamson
    • , Shawn M Gillespie
    • , Russell J H Ryan
    •  & Bradley E Bernstein
  3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Yotam Drier
    • , Matthew J Cotton
    • , Kaylyn E Williamson
    • , Shawn M Gillespie
    • , Russell J H Ryan
    • , James E Bradner
    • , Birgit Knoechel
    •  & Bradley E Bernstein
  4. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Yotam Drier
    • , Matthew J Cotton
    • , Kaylyn E Williamson
    • , Shawn M Gillespie
    • , Russell J H Ryan
    •  & Bradley E Bernstein
  5. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Michael J Kluk
    • , Christopher D Carey
    • , Scott J Rodig
    • , Lynette M Sholl
    •  & Jon C Aster
  6. Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

    • Lurdes Queimado
  7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Jun Qi
    •  & James E Bradner
  8. South Texas Accelerated Research Therapeutics (START), San Antonio, Texas, USA.

    • Michael J Wick
  9. Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

    • Adel K El-Naggar
  10. Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA.

    • Christopher A Moskaluk
  11. Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Birgit Knoechel
  12. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Birgit Knoechel


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B.K. and Y.D. designed and performed experiments and analyzed the data. B.K. and B.E.B. designed the experimental strategy and supervised the study and analysis. Y.D. carried out computational analyses. Y.D., B.K. and B.E.B. wrote the manuscript. J.C.A., M.J.C., K.E.W., S.M.G., C.D.C., S.J.R., L.M.S. and M.J.W. contributed to experiments and data analysis. A.H.A., R.J.H.R., M.J.K., W.C.F., L.Q., J.Q., J.E.B., C.A.M., A.K.E.-N. and J.E.B. provided reagents, contributed to analysis and gave conceptual advice. All authors discussed the results and implications and reviewed the manuscript.

Competing interests

J.E.B. is a scientific founder of Tensha Therapeutics, which has licensed drug-like derivatives of the JQ1 bromodomain inhibitor from the Dana-Farber Cancer Institute. The remaining authors declare no competing financial interests.

Corresponding authors

Correspondence to Birgit Knoechel or Bradley E Bernstein.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–11 and Supplementary Table 5

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  1. 1.

    Supplementary Table 1

    Rearrangements detected in six ACC primagrafts from whole-genome sequencing.

  2. 2.

    Supplementary Table 2

    MYB high-confidence peaks and associated nearby genes.

  3. 3.

    Supplementary Table 3

    Enriched annotations of MYB targets.

  4. 4.

    Supplementary Table 4

    Transcriptional regulators targeted by MYB ranked by MYB binding, with expression levels in ACC and normal gland.

  5. 5.

    Supplementary Table 6

    Primer and reporter sequences used in this study.

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