Pomalidomide, a derivative of thalidomide, is an effective treatment for multiple myeloma. The drug exerts its effects through CRBN, a component of the E3 ubiquitin ligase complex CRL4^CRBN. To search for novel factors involved in the anti-cancer activity of pomalidomide, we performed a genome-wide shRNA library screen and identified 445 genes as those affecting pomalidomide sensitivity. Genes encoding components of the ubiquitin-proteasome pathway, such as subunits of the CRL4^CRBN complex, the COP9 signalosome, and the 26S proteasome, were among the pomalidomide-affecting genes. Karyopherin beta 1 (KPNB1) was identified as a novel pomalidomide-affecting gene. KPNB1 was required for the nuclear import of CRBN and for the CRBN-directed, pomalidomide-dependent degradation of a clinically relevant substrate, the transcription factor Aiolos. By contrast, the cytoplasmic translation factor GSPT1 was degraded following treatment with the thalidomide derivative CC-885 only when CRBN was present in the cytoplasm, indicating that subcellular distribution of CRBN is critical for the efficacy of thalidomide-based medications.

泊利度胺，沙利度胺的衍生物，是治疗多发性骨髓瘤的有效方法。该药物通过CRBN发挥作用，CRBN是E3泛素连接酶复合物CRL4 ^{CRBN的组成部分}。为了寻找与pomalidomide的抗癌活性有关的新因素，我们进行了全基因组shRNA筛选，并鉴定了445个基因作为影响pomalidomide敏感性的基因。编码泛肽^酶的基因包括编码遍在蛋白-蛋白酶体途径的成分的基因，例如CRL4 ^CRBN复合体的亚基，COP9信号体和26S蛋白酶体。核转运蛋白beta 1（KPNB1）被鉴定为是一种新的影响pomalidomide的基因。KPNB1是CRBN的核输入和临床相关底物-转录因子Aiolos的CRBN定向，pomalidomide依赖性降解所必需的。相比之下，仅当在细胞质中存在CRBN时，用沙利度胺衍生物CC-885处理后，细胞质翻译因子GSPT1才被降解，这表明CRBN的亚细胞分布对于以沙利度胺为基础的药物的疗效至关重要。