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。

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.