免疫调节剂（immunomodulatory drugs，IMiDs）在临床上的广泛使用极大的提高了多发性骨髓瘤（multiple myeloma，MM）患者的治疗效果，延长了患者的生存期。然而，在复发与难治MM患者中IMiDs耐药的情况十分普遍。已有研究证实，CRBN作为IMiDs的直接靶点，其表达水平的降低与IMiDs耐药相关。我们的研究表明，转录因子LYAR可以直接结合到CRBN基因启动子区域，招募精氨酸甲基转移酶PRMT5，催化组蛋白H4发生甲基化修饰，沉默CRBN基因表达。结合MM耐药细胞株和病例分析的结果，我们发现MM出现耐药后PRMT5表达水平显著升高，从而导致CRBN表达被抑制。进一步，我们将探究PRMT5小分子抑制剂与IMiDs联用治疗MM的可能性。以上研究将阐明PRMT5在调控CRBN基因表达及MM耐药中的重要作用，为将PRMT5作为治疗靶点逆转MM耐药提供理论基础。

Extensive clinical use of immunomodulatory drugs (IMiDs) has greatly improved the outcomes of patients with multiple myeloma (MM). However, IMiDs-resistance is very common in relapsed and refractory MM patients. It has been confirmed that CRBN is a direct target of IMiDs and low CRBN expression is associated with IMiDs-resistance in MM cell lines and patients. Our study suggests that transcription factor LYAR can directly bind to the promoter region of CRBN gene, recruit arginine methyltransferase PRMT5, result in subsequent histone H4 methylation and CRBN gene silencing. Combined with the results of MM cell lines and clinical data, we found that the expression of PRMT5 was significantly increased in IMiDs-resistant MM cell lines, leading to suppressed CRBN expression. Further, we will evaluatethe effects of PRMT5 small molecule inhibitors and IMiDs combination regimen to treat MM. This study will reveal the vital role of PRMT5 in CRBN gene regulation and IMiDs resistance in MM patients, and characterize PRMT5 as a therapeutic target to overcome IMiDs resistance.