AP-1激活蛋白-1(AP-1)转录因子(TFs)与许多不同类型的癌症相关，并且在逻辑恶性肿瘤中是有前途的治疗靶点。然而，它们在多发性骨髓瘤(MM)中的作用机制仍不清楚。本研究确定并比较了MM患者和健康供者的CD138+单核细胞中AP-1家族成员JunB的mRNA和蛋白表达水平。在此基础上，我们研究了JUN/AP-1抑制剂T-5224对MM的作用。我们发现，T-5224对骨髓瘤的细胞毒性作用是由于其诱导细胞凋亡、抑制增殖和诱导细胞周期阻滞，通过增加caspase3/7的水平和同时抑制 IRF4/MYC轴。我们还注意到，通过siJunB介导的JUN/AP-1的缺失增强了MM细胞的凋亡并影响了细胞增殖。本研究使用PROMO软件预测了可能结合IRF4启动子区域的AP-1转录因子。我们证实了JunB/AP-1与IRF4之间的相关性。鉴于硼替佐米(BTZ)可以促进MM细胞中的IRF4降解，我们使用了BTZ与T-5224的联合治疗。T-5224和BTZ产生了协同效应，T-5224逆转了BTZ对MM细胞中CD138+的原发性耐药性的影响，部分原因是通过抑制IRF4/MYC轴。我们的结果表明，针对AP-1转录因子是治疗MM的有前途的策略。此外，利用T-5224同时靶向AP-1和IRF4可能是治疗这种临床上具有挑战性的MM亚群的协同策略。版权所有 © 2023. 由Elsevier B.V.出版。

The activating protein-1 (AP-1) transcription factors (TFs) have been associated with many different cancer types and are promising therapeutic targets in logical malignancies. However, the mechanisms of their role in multiple myeloma (MM) remain elusive. The present study determined and compared the mRNA and protein expression levels of the AP-1 family member JunB in CD138+ mononuclear cells from MM patients and healthy donors. Herein, we investigated the effect of T-5224, an inhibitor of JUN/AP-1, on MM. We found that the cytotoxicity of T-5224 toward myeloma is due to its ability to induce cell apoptosis, inhibit proliferation, and induce cell cycle arrest by increasing the levels of caspase3/7 and concomitantly inhibiting the IRF4/MYC axis. We also noticed that siJunB-mediated deletion of JUN/AP-1 enhanced MM cell apoptosis and affected cell proliferation. The software PROMO was used in the present study to predict the AP-1 TF that may bind the promoter region of IRF4. We confirmed the correlation between JunB/AP-1 and IRF4. Given that bortezomib (BTZ) facilitates IRF4 degradation in MM cells, we applied combination treatment of BTZ with T-5224. T-5224 and BTZ exerted synergistic effects, and T-5224 reversed the effect of BTZ on CD138+ primary resistance in MM cells, in part due to suppression of the IRF4/MYC axis. Our results suggest that targeting AP-1 TFs is a promising therapeutic strategy for MM. Additionally, targeting both AP-1 and IRF4 with T-5224 may be a synergistic therapeutic strategy for this clinically challenging subset of MM.Copyright © 2023. Published by Elsevier B.V.