Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma
Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma
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DOI：
10.7554/elife.19432
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发表时间：
2016-01-05
期刊：
影响因子：
7.7
通讯作者：
Sims, Robert J., III
中科院分区：
文献类型：
--
作者：
Conery, Andrew R.;Centore, Richard C.;Sims, Robert J., III
染色质共调节因子的药理学抑制代表了通过选择性减弱基因表达来调节致癌信号传导的经临床验证的策略。在这里，我们证明CBP/EP 300布罗莫结构域抑制优先消除多发性骨髓瘤细胞系的活力。通过CBP/EP 300布罗莫结构域抑制选择性靶向多发性骨髓瘤细胞系是淋巴细胞特异性转录因子IRF 4的直接转录抑制的结果，IRF 4对骨髓瘤细胞的活力至关重要，同时也抑制了IRF 4靶基因c-MYC。IRF 4或MYC的异位表达拮抗CBP/EP 300布罗莫结构域抑制的表型和转录效应，突出了IRF 4/MYC轴作为其作用机制的关键组分。这些发现表明CBP/EP 300布罗莫结构域抑制代表了靶向依赖于IRF 4网络的多发性骨髓瘤和其他淋巴恶性肿瘤的可行治疗策略。
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.