Dissecting the impact of bromodomain inhibitors on the Interferon Regulatory Factor 4-MYC oncogenic axis in multiple myeloma.
Dissecting the impact of bromodomain inhibitors on the Interferon Regulatory Factor 4-MYC oncogenic axis in multiple myeloma.
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DOI：
10.1002/hon.3016
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发表时间：
2022-08
影响因子：
3.3
通讯作者：
Mancini, Erika J.
中科院分区：
文献类型：
--
作者：
Agnarelli, Alessandro;Mitchell, Simon;Caalim, Gillian;Wood, C. David;Milton-Harris, Leanne;Chevassut, Timothy;West, Michelle J.;Mancini, Erika J.
B细胞前体细胞命运决定因子干扰素调节因子4(IRF4)在多发性骨髓瘤(MM)的发病和发展中发挥关键作用，MM是一种目前无法治愈的浆细胞恶性肿瘤。IRF4的异常表达和与癌基因myc的正向自动调节环的建立，驱动了MM特异的基因表达程序，导致恶性未成熟浆细胞的异常扩张。靶向IRF4-MYC致癌环有可能为MM提供一种选择性和有效的治疗方法。在这里，我们评估了溴域抑制剂通过联合抑制已知的表观遗传调节因子BRD4和CBP/EP300来靶向IRF4-MYC轴的使用。虽然所有的抑制剂都能诱导细胞死亡，但我们没有发现靶向这两种调控因子对MM细胞系的活性有协同作用。重要的是，对于所有的抑制剂，在长达72小时的时间内，我们检测到IRF4 mRNA的减少，但IRF4蛋白表达或下游靶基因的mRNA水平的下降是有限的。这表明，与先前提出的那样，抑制剂诱导的细胞活力丧失不是通过减少IRF4蛋白的表达来调节的。进一步分析发现，骨髓瘤细胞中存在较长的IRF4蛋白半衰期。为了支持我们的实验观察，MM的基因网络建模表明，溴域抑制主要是通过MYC而不是IRF4施加的。这些发现表明，尽管IRF4和MYC之间存在自动反馈的正向调控环，但溴域抑制剂在MM中不能有效地靶向IRF4，新的治疗策略应该专注于直接抑制或降解IRF4。
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 program 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 h, 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 modeling 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.
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影响因子：
11.4
作者：
Chng, W-J;Huang, G. F.;Chung, T. H.;Ng, S. B.;Gonzalez-Paz, N.;Troska-Price, T.;Mulligan, G.;Chesi, M.;Bergsagel, P. L.;Fonseca, R.
通讯作者：
Fonseca, R.
影响因子：
64.8
作者：
Shaffer, Arthur L.;Emre, N. C. Tolga;Staudt, Louis M.
通讯作者：
Staudt, Louis M.
影响因子：
56.9
作者：
Lin, Y;Wong, KK;Calame, K
通讯作者：
Calame, K
影响因子：
11.4
作者：
Morelli E;Leone E;Cantafio ME;Di Martino MT;Amodio N;Biamonte L;Gullà A;Foresta U;Pitari MR;Botta C;Rossi M;Neri A;Munshi NC;Anderson KC;Tagliaferri P;Tassone P
通讯作者：
Tassone P
影响因子：
10.1
作者：
Díaz T;Rodríguez V;Lozano E;Mena MP;Calderón M;Rosiñol L;Martínez A;Tovar N;Pérez-Galán P;Bladé J;Roué G;de Larrea CF
通讯作者：
de Larrea CF