CRBN基因与免疫调节剂治疗多发性骨髓瘤耐药机制的相关性研究  

Association of CRBN Gene with Immunomodulatory Drug Resistance in Multiple Myeloma——Review

作　　者：蔡倩倩[1] 李剑[1] 

机构地区：[1]中国医学科学院、北京协和医学院,北京协和医院血液内科,北京100730

出　　处：《中国实验血液学杂志》2015年第3期892-897,共6页Journal of Experimental Hematology

摘　　要：CRBN(cereblon)位于3号染色体短臂,其编码的CRBN蛋白参与构成E3泛素连接酶,通过将底物蛋白泛素化进而被蛋白酶体系统降解,发挥生物学效应。目前常用的CRBN基因和蛋白的检测方法主要有qRT-PCR、免疫组织化学技术和Western blot等,但尚缺乏标准化和规范化。研究已证实,CRBN是免疫调节剂(IMi D)治疗多发性骨髓瘤的直接结合靶点,在抗肿瘤细胞增殖、诱导骨髓瘤细胞凋亡、抗新生血管形成、增强T细胞和NK细胞免疫活性、抑制细胞间黏附分子表达中发挥重要作用。近年来多项体内及体外的研究发现,CRBN基因低表达或缺失可能与IMi D治疗多发性骨髓瘤的耐药性相关,且其基因表达水平可能与多发性骨髓瘤患者的预后相关。最近研究发现,IKZF1、IKZF3、IRF4、C/EBPβ等蛋白以及Wnt/catenin信号通路等可能也与IMi D的耐药机制相关。Human CRBN （cereblon） gene is located on chromosome 3 at 3p26 and its encoding protein is a member of E3 ubiquitin ligase complex （ composed of CRBN, DDB1, CUL4A and ROC1 ）. The E3 ubiquitin ligase complex functions in the ubiquitin-proteasome protein degradation pathway and attaches polyubiquitin chains to substrate proteins for degradation via the protease complex. Currently, there are no standardized assays for CRBN gene and protein measurement although quantitative reverse transcription polymerase chain reaction （qRT-PCR）, immunohistochemistry and Western blot are widely used. CRBN has been identified as a direct target for immunomo-dulatory drugs （ IMiD ） and plays a significant role in anti-proliferation, pro-apoptotic effects, anti-angiogenic activities, immunomodulatory activities and intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells. Recently, clinical data show that majority of the multiple myeloma patients treated with IMiD develop drug-resistance over time by unknown mechanisms. Fortunately, various in vivo and in vitro studies have revealed that the decreased CRBN expression or CRBN deletion is associated with resistance to IMiD in treating multiple myeloma, and CRBN expression levels may have a prognostic significance. Furthermore, the most recently discovered protein IKZF1, IKZF3, IRF4, C/EBPβ and Wnt/catenin signaling pathways may also be closely related to IMiD resistance in myeloma.

关 键 词：CRBN(cereblon) 免疫调节剂 多发性骨髓瘤 耐药 

分 类 号：R733.3[医药卫生—肿瘤] R738.1[医药卫生—临床医学]