来那度胺可以利用CRL4（CRBN）泛素连接酶来泛素化降解对多发性骨髓瘤细胞存活至关重要的两个转录因子IKZF1和IKZF3蛋白，最终导致骨髓瘤细胞毒性。我们发现c-Abl激酶磷酸化CRL4的接头蛋白DDB1，促进其结合一个小的调节蛋白DDA1，进而增强CRL4底物的泛素化。所以，激活c-Abl激酶会增强骨髓瘤细胞对来那度胺的敏感性。我们近期的研究显示CSN复合体可能参与了c-Abl激酶对CRL4的调控。因此，我们提出假设：c-Abl激酶通过解除CSN复合体对CRL4泛素化连接酶活性的抑制，增加了CRL4的活性，进而增强了多发性骨髓瘤细胞对来那度胺的敏感性。我们的研究将揭示c-Abl激酶通过CSN复合体影响CRL4泛素连接酶活性进而调控多发性骨髓瘤细胞对来那度胺敏感性的机制，为临床上更有效地使用此类药物以及开发新一代的免疫调节药物具有重要的指导意义。

Lenalidomide hijacks the CRL4(CRBN) ubiquitin ligase to promote the ubiquitination and degradation of IKZF1 and IKZF3, two transcription factors essential for multiple myeloma (MM) cell survival. We found that the c-Abl non-receptor kinase phosphorylates DDB1, the adaptor protein of CRL4 ubiquitin ligase, at residue Y316 to recruit a small regulatory protein DDA1, leading to increased substrate ubiquitination. Thus, activation of c-Abl kinase can sensitize MM cells to lenalidomide-induced cytotoxicity. Recently, our study suggests that COP9 signalasome (CSN complex) may be involved in the regulation of CRL4 ubiquitin ligase by c-Abl. We therefore hypothesize that c-Abl kinase increases the activity of CRL4 and sensitizes MM cells to lenalidomide by promoting the escape of CRL4 from CSN repression. Our study will shed light into how c-Abl kinase regulates the sensitivity of MM cells to lenalidomide, therefore providing important reference for its better clinical targeting efficacy and the development of next generation of immunomodulatory drugs.