剪切因子RBM39在多发性骨髓瘤中的病理机制研究

异常的可变剪切是癌症的新标志，异常的剪切因子在多种实体肿瘤中已有开创性的探究，但是多发性骨髓瘤（MM）中异常的剪切因子仍缺乏相关研究。前期通过广泛筛选MM中异常表达的剪切因子，我们发现RBM39在MM中高表达且与临床不良预后呈正相关；实验表明RBM39能够显著促进MM细胞的增殖，抑制其凋亡；进一步实验证实RBM39能够影响BIM（Bcl-2-Like Protein 11）的可变剪切，增加其异常转录本的转录。由此我们提出：RBM39通过调控BIM的可变剪切促进MM的发生发展。围绕上述假说，我们将开展以下研究：应用CLIP-seq以及EMSA技术明确RBM39结合的motif；证实RBM39对BIM可变剪切的调控；体内外实验证实BIM异常转录本的功能；筛选RBM39抑制剂及进行靶向RBM39治疗MM的效应研究。课题研究结果有助于进一步认识MM的病理机制并为MM治疗提供理论依据及新的分子靶点。

Aberrant alternative splicing is known as a new hallmark of cancer, and has breakthrough significance in researches on solid tumors. However, previous studies relevant to multiple myeloma (MM) were scarce. From the extensive screening study, we have found the splicing factor RBM39 is widely over-expressed in MM and predominantly correlated with poor prognosis. The results have showed that RBM39 significantly promoted proliferation and inhibited apoptosis in varieties of MM cells. Further experiments have confirmed that RBM39 affected the splicing of BIM (Bcl-2-Like Protein 11) and increased the transcription of its abnormal transcript. We make hypothesis that RBM39 accelerates the occurrence and development of MM via regulating alternative splicing of BIM. Therefore, we intend to continue studies as follows: using CLIP-seq and EMSA techniques to clarify the motif of RBM39, confirming the regulation of RBM39 on variable splicing of BIM, certifying the function of abnormal transcript of BIM through in vitro and in vivo experiments, screening out inhibitors targeting RBM39 and evaluating their effects in MM cells. All studies will help us discover the pathogenesis of MM, provide theoretical basis and new molecular targets for the treatment of MM.