Dissecting the impact of bromodomain inhibitors on the IRF4-MYC oncogenic axis in multiple myeloma

Agnarelli, Alessandro, Mitchell, Simon, Caalim, Gillian, Wood, C David, Milton-Harris, Leanne, Chevassut, Timothy, West, Michelle J and Mancini, Erika J (2022) Dissecting the impact of bromodomain inhibitors on the IRF4-MYC oncogenic axis in multiple myeloma. Hematological Oncology. pp. 1-13. ISSN 0278-0232

[img] PDF - Published Version
Available under License Creative Commons Attribution.

Download (1MB)
[img] PDF - Accepted Version
Available under License All Rights Reserved.

Download (5MB)

Abstract

B-cell progenitor fate determinant interferon regulatory factor 4 (IRF4) exerts key roles in the pathogenesis and progression of multiple myeloma (MM), a currently incurable plasma cell malignancy. Aberrant expression of IRF4 and the establishment of a positive auto-regulatory loop with oncogene MYC, drives a MM specific gene-expression programme leading to the abnormal expansion of malignant immature plasma cells. Targeting the IRF4-MYC oncogenic loop has the potential to provide a selective and effective therapy for MM. Here we evaluate the use of bromodomain inhibitors to target the IRF4-MYC axis through combined inhibition of their known epigenetic regulators, BRD4 and CBP/EP300. Although all inhibitors induced cell death, we found no synergistic effect of targeting both of these regulators on the viability of MM cell-lines. Importantly, for all inhibitors over a time period up to 72 hours, we detected reduced IRF4 mRNA, but a limited decrease in IRF4 protein expression or mRNA levels of downstream target genes. This indicates that inhibitor-induced loss of cell viability is not mediated through reduced IRF4 protein expression, as previously proposed. Further analysis revealed a long half-life of IRF4 protein in MM cells. In support of our experimental observations, gene network modelling of MM suggests that bromodomain inhibition is exerted primarily through MYC and not IRF4. These findings suggest that despite the autofeedback positive regulatory loop between IRF4 and MYC, bromodomain inhibitors are not effective at targeting IRF4 in MM and that novel therapeutic strategies should focus on the direct inhibition or degradation of IRF4. This article is protected by copyright.

Item Type: Article
Keywords: BET/BRD4, CBP/EP300, Dual inhibition, IRF4, MYC, Multiple Myeloma
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
School of Life Sciences > Biochemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 17 May 2022 07:20
Last Modified: 06 Jun 2022 15:00
URI: http://sro.sussex.ac.uk/id/eprint/105951

View download statistics for this item

📧 Request an update