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

eLife

Adrianne Neiss¹  Archana Bommi-Reddy¹  Jennifer A Mertz¹  Charlie Hatton¹  Eneida Pardo¹  Robert J Sims III¹  Peter Sandy¹  Andrew R Conery¹  Shivangi Joshi¹  Laura Zawadzke¹  Richard C Centore¹  Barbara M Bryant¹  Patricia J Keller¹  Kerry L Spillane¹  Karen E Gascoigne² 

[1] Constellation Pharmaceuticals, Cambridge, United States;Genentech, South San Francisco, United States;

关键词: CBP;    EP300;    bromodomain;    IRF4;    MYC;    myeloma;   

DOI  :  10.7554/eLife.10483

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown