NEK2在多发性骨髓瘤染色体不稳定性中的分子机制研究

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by cytogenetic abonomities. Our prelimilary data demostrated 10 increased chromosome instability (CIN) signatures are associated with drug resistance and poor prognosis. Over expression of NEK2,one of the CIN genes,plays an important role in the drug resistance,CIN and outcome of MM. High expression of NEK2 induced drug resistance mainly through activation of the efflux pumps. However, the underlying mechanisms of NEK2 involved in CIN and its significance in MM development and progression are not well understood. The aims of this application are to perform the dedicated research using at dignosis, relapse and sequential patient specimens in order to refine the relationship between NEK2 and CIN in MM; to elucidate the role of NEK2 in cell cycle, cell proliferation, centrocome seperation and chromosone abonomities in vitro;to further our understanding of NEK2 dependent AKT/Wnt and β-catenin signal pathways involved in CIN and proliferation in MM; finally, to elucidate the important role of NEK2 related to CIN in the initiation,progression and relapse of MM and to guide the development of novel therapies and provide a prognosis and a new target in MM treatment.

多发性骨髓瘤（multiple myeloma,MM）是一类以细胞遗传学异常为特征的克隆性B细胞的恶性肿瘤。我们的前期研究发现共有10个染色体不稳定性(chromosome instability,CIN)基因与MM的耐药及复发相关,其中NEK2在MM的耐药、CIN及预后起着重要作用。NEK2主要通过上调多药耐药蛋白参与MM的耐药，但是NEK2通过何种途径参与MM的CIN，分子机制不详。本项目拟在初诊、复发及序贯的多发性骨髓瘤患者中检测NEK2与CIN相关性；体外实验分析NEK2与细胞周期、细胞增殖、中心体分离、染色体畸变等的相关性；阐明在MM中NEK2如何通过AKT/Wnt 和β-catenin参与CIN的分子机制。本课题的开展不仅会揭示NEK2参与CIN在MM发生、发展及复发中的重要作用，也将为MM的预后及治疗提供更为准确的分子靶标。

多发性骨髓瘤（Multiple Myeloma, MM）是一种常见的血液系统恶性肿瘤，其复发与耐药是目前临床的主要问题。而p53缺失在复发耐药的病人中起到了相当重要的作用， 前期GEP数据分析发现NEK2作为一个MM中关键的耐药基因与p53具有显著相关性，进而本项目通过CHIP，荧光素酶报告基因等明确了p53对NEK2的负调控作用，体外功能试验发现p53与NEK2的双重打击能够促进MM细胞的增殖，增加MM细胞的染色体不稳定性，动物实验证实p53与NEK2的双重打击能够使细胞成瘤速度加快。随后，对NEK2耐药机制的研究发现，NEK2能够通过磷酸化BCL2释放Beclin1，促进自噬的发生，进而导致MM耐药的出现。本项目从体内外探讨了p53缺失与NEK2表达增加在多发性骨髓瘤中的重要作用，为进一步阐明MM的复发耐药机制提供了帮助，同时也为p53缺失的MM病人的治疗提供了一定的理论基础与临床指导。