Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma
oleh: 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
| Format: | Article |
|---|---|
| Diterbitkan: | eLife Sciences Publications Ltd 2016-01-01 |
Deskripsi
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.