RNA m6A阅读器IGF2BP3通过CKS1B mRNA促进伴有染色体1q21扩增的多发性骨髓瘤细胞增殖的机制研究

染色体1q21拷贝数扩增 (1q21 gain) 是多发性骨髓瘤中最常见的不良细胞遗传学异常之一，该亚群患者异质性强，亟需发现进一步分层的有效预后因子。我们前期工作提示RNA m6A阅读器蛋白IGF2BP3可结合CKS1B mRNA，促进1q21 gain骨髓瘤细胞的增殖 (2019年美国IMW大会壁报交流)。现拟开展如下工作：①构建伴有1q21 gain骨髓瘤细胞转录组m6A修饰图谱，明确CKS1B mRNA中具有m6A修饰的具体位点；②探究IGF2BP3与CKS1B mRNA是否通过m6A位点结合以及二者具体结合位点；③明确IGF2BP3是否通过增加CKS1B mRNA稳定性以及促进核糖体内CKS1蛋白的翻译，最终达到调控CKS1蛋白表达的目的；④小鼠体内实验证实假说；⑤探索1q21 gain MM患者标本CKS1与IGF2BP3蛋白表达水平和预后的关系。

Chromosome 1q21 gain is one of the most common adverse cytogenetic abnormalities in multiple myeloma. This subgroup of patients is highly heterogeneous. It is urgent to find effective prognostic factors for further stratification in these MM patients. Our previous work suggested that the RNA m6A reader IGF2BP3 could bind to CKS1B mRNA and promote the proliferation of myeloma cells with 1q21 gain (2019 IMW Conference Poster held in the United States). The following work is planned to be carried out: ①To clarify the specific sitse of m6A modification in CKS1B mRNA by constructing the m6A modification map of myeloma cell line with 1q21 gain; ②To explore the specific combination sites between IGF2BP3 protein and CKS1B mRNA; ③To clarify whether IGF2BP3 regulates the CKS1 protein level by increasing the stability of CKS1B mRNA and promoting the translation of CKS1 protein in ribosomes; ④To confirm these hypothesis by experiments in vivo; ⑤To explore the relationship between CKS1 protein and IGF2BP3 protein and the prognosis of MM patients with 1q21 gain.