1. Chromosomes and Gene Expression
  2. Cancer Biology
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Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

  1. Andrew R Conery
  2. Richard C Centore
  3. Adrianne Neiss
  4. Patricia J Keller
  5. Shivangi Joshi
  6. Kerry L Spillane
  7. Peter Sandy
  8. Charlie Hatton
  9. Eneida Pardo
  10. Laura Zawadzke
  11. Archana Bommi-Reddy
  12. Karen E Gascoigne
  13. Barbara M Bryant
  14. Jennifer A Mertz
  15. Robert J Sims  Is a corresponding author
  1. Constellation Pharmaceuticals, United States
  2. Genentech, United States
Research Article
  • Cited 67
  • Views 5,267
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Cite this article as: eLife 2016;5:e10483 doi: 10.7554/eLife.10483

Abstract

Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Selective targeting of multiple myeloma cell lines through CBP/EP300 bromodomain inhibition is the result of direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4, which is essential for the viability of myeloma cells, and the concomitant repression of the IRF4 target gene c-MYC. Ectopic expression of either IRF4 or MYC antagonizes the phenotypic and transcriptional effects of CBP/EP300 bromodomain inhibition, highlighting the IRF4/MYC axis as a key component of its mechanism of action. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.

Article and author information

Author details

  1. Andrew R Conery

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Andrew R Conery, Employee of Constellation Pharmaceuticals.

  2. Richard C Centore

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Richard C Centore, Employee of Constellation Pharmaceuticals.

  3. Adrianne Neiss

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Adrianne Neiss, Employee of Constellation Pharmaceuticals.

  4. Patricia J Keller

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Patricia J Keller, Employee of Constellation Pharmaceuticals.

  5. Shivangi Joshi

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Shivangi Joshi, Employee of Constellation Pharmaceuticals.

  6. Kerry L Spillane

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Kerry L Spillane, Employee of Constellation Pharmaceuticals.

  7. Peter Sandy

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Peter Sandy, Employee of Constellation Pharmaceuticals.

  8. Charlie Hatton

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Charlie Hatton, Employee of Constellation Pharmaceuticals.

  9. Eneida Pardo

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Eneida Pardo, Employee of Constellation Pharmaceuticals.

  10. Laura Zawadzke

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Laura Zawadzke, Employee of Constellation Pharmaceuticals.

  11. Archana Bommi-Reddy

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Archana Bommi-Reddy, Employee of Constellation Pharmaceuticals.

  12. Karen E Gascoigne

    Genentech, South San Francisco, United States
    Competing interests
    Karen E Gascoigne, Employee of Genentech.

  13. Barbara M Bryant

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Barbara M Bryant, Employee of Constellation Pharmaceuticals.

  14. Jennifer A Mertz

    Constellation Pharmaceuticals, Cambridge, United States
    Competing interests
    Jennifer A Mertz, Employee of Constellation Pharmaceuticals.

  15. Robert J Sims

    Constellation Pharmaceuticals, Cambridge, United States
    For correspondence
    robert.sims@constellationpharma.com
    Competing interests
    Robert J Sims, Employee of Constellation Pharmaceuticals.

Reviewing Editor

  1. Scott A Armstrong, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: July 30, 2015
  2. Accepted: January 4, 2016
  3. Accepted Manuscript published: January 5, 2016 (version 1)
  4. Version of Record published: February 23, 2016 (version 2)
  5. Version of Record updated: July 14, 2016 (version 3)

Copyright

© 2016, Conery 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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