MALT1调控BCMA/NF-κB级联信号在多发性骨髓瘤发病中的作用及机制研究

Multiple myeloma (MM) is an incurable hematologic cancer of plasma cells. BCMA (B-cell maturation antigen) exclusively expressed on all MM cells and patient MM cells at high level. Recently, targeting BCMA immunotherapies have received an effective short-term outcome of MM patients, particularly CAR-T (chimeric antigen receptor-expressing T cells) targeting BCMA. However, it also encouters relapse or poor long-term outcome.the relevant detailed mechanism of BCMA in the progression of MM has rarely been reported and limits designing new therapeutic regimen combination with CAR-T. We found the inhibiting MALT1 could suppresses the activation of NF-kB by BCMA inducing through screening and analyzing, and decreases the proliferatio of MM. In this project, we will usage of MALT1 inhibitor and MALT1 knockout, APRIL stimulation or BCMA overexpressed, from in vitro to in vivo, explore the function of MALT1 in the BCMA/NF-kB signaling pathway, and illuminate the role of MALT1 in the pathogenesis of MM. The study will offer more theoretical foundation for immunotherapies targeting BCMA, introduce MALT1 as a target in clinical therapy for MM patients and trigger the synergistic anti-MM activity combined with targeting BCMA immunotherapies.

多发性骨髓瘤是起源于浆细胞的恶性血液肿瘤，至今仍不可治愈。BCMA在骨髓瘤中特异性高表达，近年来以其为靶点的免疫治疗，尤其靶向BCAM的CRA-T细胞疗法在多发性骨髓瘤患者的临床试验中获得了良好的疗效，但也面临复发及长期预后不佳的问题。而BCMA在多发性骨髓瘤中的调控通路知之甚少，限制了与CAR-T免疫疗法进行联合治疗方案的设计。我们前期通过筛选发现特异性抑制MALT1可阻断BCMA活化NF-κB，并抑制骨髓瘤的增殖。本项目拟在前期工作基础上，敲除MALT1基因和利用MALT1抑制剂，结合APRIL外源刺激或BCMA过表达，从体外到体内，探索MALT1在BCMA/NF-κB级联信号中的作用机制，阐明MALT1在调控骨髓瘤进展中的作用。项目如期完成，将为BCMA作为免疫治疗靶点提供更充足理论依据，有望将MALT1引入骨髓瘤的临床靶向治疗，进一步增强BCMA靶向治疗多发性骨髓瘤的疗效。

多发性骨髓瘤是起源于浆细胞的恶性血液肿瘤，随着Car-T等免疫疗法的发展，患者的生存率得到了极大的提高，但是仍是不可治愈的疾病。尤其是靶向BCMA的CAR-T细胞疗法，患者在获得良好疗效的同时，仍有部分患者面临复发及长期预后不佳的问题。我们的研究发现MALT1在BCMA诱导的NF-kB通路活化的过程中起到关键作用，特异性的敲低MALT1可有效的抑制骨髓瘤细胞的增殖，使用MALT1特异性抑制剂Mi-2可以显著的杀伤骨髓瘤细胞，并且体内实验进一步证实Mi-2可明显的延长荷瘤小鼠的生存期。在本项目的资助下我们发现m6A甲基化转移酶METTL3也参与调控多发性骨髓瘤NF-kB通路活化，促进肿瘤进展。具体内容概述如下：（1）相比较健康的PBMC细胞，MALT1在多发性骨髓瘤细胞中表达水平较高；（2）MALT1敲低后抑制多发性骨髓瘤细胞的增殖及克隆形成能力；（3）使用MALT1特性抑制剂Mi-2可以抑制骨髓瘤细胞增殖，诱导凋亡，抑制骨髓瘤细胞因子分泌及破骨细胞生成；（4）MALT1敲除延长小鼠的生存期；（5）MALT1活性被抑制时可降低P65的磷酸化水平及BCMA诱导的NF-kB通路的活化；（6）METTL3敲低可显著的抑制多发性骨髓瘤细胞增殖，克隆形成，诱导凋亡；（7）初步发现METTL3可以通过IkB介导p65磷酸化的水平。综上，通过本研究基本阐明了MALT1通过NF-kB通路介导多发性骨髓瘤增殖，另一方面本研究发现METTL3也参与多发性骨髓瘤细胞中NF-kB通路的活化。以上的研究为靶向NF-kB治疗多发性骨髓瘤提供更多的理论基础和新的治疗靶点。