eLife (Jan 2016)

Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma

  • Andrew R Conery,
  • Richard C Centore,
  • Adrianne Neiss,
  • Patricia J Keller,
  • Shivangi Joshi,
  • Kerry L Spillane,
  • Peter Sandy,
  • Charlie Hatton,
  • Eneida Pardo,
  • Laura Zawadzke,
  • Archana Bommi-Reddy,
  • Karen E Gascoigne,
  • Barbara M Bryant,
  • Jennifer A Mertz,
  • Robert J Sims III

DOI
https://doi.org/10.7554/eLife.10483
Journal volume & issue
Vol. 5

Abstract

Read online

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.

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