Abstract：
Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3\'-untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU-binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn-humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation.
摘要：
多发性骨髓瘤（MM）是骨髓中无法治愈的浆细胞癌。免疫调节药物，如来那度胺（LEN）和泊马度胺，是MM治疗中的骨干药物，LEN耐药性常见于MM临床。在这项研究中,我们提出，异质核核糖核蛋白U（hnRNPU）通过调节靶mRNA翻译影响MM对LEN的抗性。hnRNPULowMM细胞表现出上调的CRBN和IKZF1蛋白，添加LEN后严格IKZF1/3蛋白降解，并增加对LEN的敏感性。RNA下拉测定和RNA电泳迁移率变化测定显示hnRNPU与CRBN和IKZF1mRNA的3'-非翻译区结合。蔗糖梯度分析表明hnRNPU特异性调节CRBN和IKZF1mRNA翻译。hnRNPU通过具有hnRNPU结合位点的小RNA与其靶mRNA的竞争恢复了MM对LEN的敏感性。在通过将Crbn人源化鼠5TGM1细胞接种到CrbnI391V/小鼠中构建的免疫活性MM小鼠模型中证实了体内hnRNPU功能。总的来说,这项研究提示了LEN敏感性的新机制，其中hnRNPU抑制CRBN和IKZF1mRNA翻译。
