文章：

CRL4^CRBN底物Ikaros和Aiolos的降解速率通过调控c-Myc和IRF4，决定了来那度胺和泊马度胺在多发性骨髓瘤细胞中的差异活性

Rate of CRL4^CRBN substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4

原文发布日期：2015-10-02

DOI: 10.1038/bcj.2015.66

类型: Original Article

开放获取: 是

英文摘要：

Recent discoveries suggest that the critical events leading to the anti-proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets.

摘要翻译： 

最新研究发现，来那度胺和泊马度胺等IMiD免疫调节剂在多发性骨髓瘤细胞中发挥抗增殖活性的关键机制，是通过Cereblon介导的底物蛋白Ikaros（IKZF1）和Aiolos（IKZF3）的泛素化及蛋白酶体降解实现的。动力学分析表明，Ikaros与Aiolos的下调或降解会引发c-Myc的特异性顺序下调，继而导致IRF4下调，最终抑制细胞增殖并诱导凋亡。值得注意的是，要实现持续的增殖抑制和细胞死亡，需要维持Ikaros、Aiolos、c-Myc或IRF4表达的长期抑制。此外，研究证实来那度胺或泊马度胺抑制效力的差异与Ikaros和Aiolos降解的半最大速率相关，而非最终降解程度。最后我们观察到，与原代正常浆细胞相比，这四种转录因子在多发性骨髓瘤原代样本中均呈现高表达。这些发现揭示了Ikaros和Aiolos与c-Myc、IRF4病理失调之间的功能关联，并通过底物降解动力学及其下游靶点调控机制，为阐释来那度胺与泊马度胺的相对疗效提供了新的理论依据。

原文链接：

Rate of CRL4^CRBN substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4