Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma

  1. Gerard L Brien  Is a corresponding author
  2. David Remillard
  3. Junwei Shi
  4. Matthew L Hemming
  5. Jonathon Chabon
  6. Kieran Wynne
  7. Eugène T Dillon
  8. Gerard Cagney
  9. Guido Van Mierlo
  10. Marijke P Baltissen
  11. Michiel Vermeulen
  12. Jun Qi
  13. Stefan Fröhling
  14. Nathanael S Gray
  15. James E Bradner
  16. Christopher R Vakoc
  17. Scott A Armstrong  Is a corresponding author
  1. Dana Farber Cancer Institute, United States
  2. University of Pennsylvania, United States
  3. University College Dublin, Ireland
  4. Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Netherlands
  5. Dana-Farber Cancer Institute, United States
  6. German Cancer Consortium (DKTK), Germany
  7. Cold Spring Harbor Laboratory, United States

Abstract

Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.

Data availability

All next-generation sequencing datasets generated in association with this work have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE113229

The following data sets were generated

Article and author information

Author details

  1. Gerard L Brien

    Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, United States
    For correspondence
    gbrien@tcd.ie
    Competing interests
    No competing interests declared.
  2. David Remillard

    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Junwei Shi

    Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  4. Matthew L Hemming

    Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Jonathon Chabon

    Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  6. Kieran Wynne

    School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
    Competing interests
    No competing interests declared.
  7. Eugène T Dillon

    School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
    Competing interests
    No competing interests declared.
  8. Gerard Cagney

    School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
    Competing interests
    No competing interests declared.
  9. Guido Van Mierlo

    Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  10. Marijke P Baltissen

    Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  11. Michiel Vermeulen

    Department of Molecular Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  12. Jun Qi

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  13. Stefan Fröhling

    German Cancer Consortium (DKTK), Heidelberg, Germany
    Competing interests
    No competing interests declared.
  14. Nathanael S Gray

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403
  15. James E Bradner

    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  16. Christopher R Vakoc

    Cold Spring Harbor Laboratory, New York, United States
    Competing interests
    No competing interests declared.
  17. Scott A Armstrong

    Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, United States
    For correspondence
    Scott_armstrong@dfci.harvard.edu
    Competing interests
    Scott A Armstrong, is a consultant and/or shareholder for Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Syros Pharmaceuticals, OxStem Oncology, ProQR and Accent Therapeutics. Also receives research support from Janssen, Novartis, and AstraZeneca..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9099-4728

Funding

National Cancer Institute (CA176745)

  • Scott A Armstrong

Alex's Lemonade Stand Foundation for Childhood Cancer

  • Scott A Armstrong

European Molecular Biology Organization (ALTF-1235-2015)

  • Gerard L Brien

Irish Cancer Society (CRF18BRI)

  • Gerard L Brien

National Cancer Institute (CA066996)

  • Scott A Armstrong

National Cancer Institute (CA204915)

  • Scott A Armstrong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mouse experiments were performed according to approved institutional animal care and use committee (IACUC) protocols at the Dana Farber Cancer Institute.

Reviewing Editor

  1. Maarten van Lohuizen, The Netherlands Cancer Institute, Netherlands

Version history

  1. Received: August 21, 2018
  2. Accepted: November 11, 2018
  3. Accepted Manuscript published: November 15, 2018 (version 1)
  4. Version of Record published: December 3, 2018 (version 2)

Copyright

© 2018, Brien et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Gerard L Brien
  2. David Remillard
  3. Junwei Shi
  4. Matthew L Hemming
  5. Jonathon Chabon
  6. Kieran Wynne
  7. Eugène T Dillon
  8. Gerard Cagney
  9. Guido Van Mierlo
  10. Marijke P Baltissen
  11. Michiel Vermeulen
  12. Jun Qi
  13. Stefan Fröhling
  14. Nathanael S Gray
  15. James E Bradner
  16. Christopher R Vakoc
  17. Scott A Armstrong
(2018)
Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma
eLife 7:e41305.
https://doi.org/10.7554/eLife.41305

Share this article

https://doi.org/10.7554/eLife.41305

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