在多发性骨髓瘤中，染色体不稳定性预示着疾病的发生、进展、耐药性的产生以及预后的不良， 然而其发生的分子机制尚不清楚。最新研究表明，STAG2基因突变可导致实体瘤染色体不稳定性的发生，本课题组前期曾在多发性骨髓瘤患者骨髓中，检测到新的STAG2基因突变106135 T>C(T335I)，且在HCT116细胞内敲入该点突变，可以引起明显的染色体不稳定性的发生，从而我们推测“STAG2基因突变参与多发性骨髓瘤染色体不稳定性的发生”。本课题以多发性骨髓瘤细胞株为研究对象， 在STAG2过表达/敲除后，通过免疫共沉淀及免疫荧光技术，研究STAG2基因突变对染色体黏连蛋白复合体的功能、分裂中期姐妹染色单体的凝聚力和分裂后期姐妹染色体分离的影响，从而阐明STAG2基因突变参与多发性骨髓瘤染色体不稳定性的分子学机制，进一步揭示多发性骨髓瘤的发病机制，为多发性骨髓瘤的有效防治提供新思路及药物作用的新靶点。

In cytogenetic level, chromosomal instability (CIN) is a hallmark of multiple myeloma (MM). Majority of studies suggest that CIN is associated with advanced stages of disease, clone evolution, aggressive clinical course and poor prognosis. However, the mechanisms leading to CIN are at present unclear. The latest research shows that mutational inactivation of the STAG2 gene, a subunit of cohesin complex, can cause CIN in solid tumors, such as melanoma, Ewing's sarcoma and glioblastoma. Our previous investigation showed that a new mutation of STAG2, 106135T>C (T335I), was detected in MM patients. So we hypothesize that mutational inactivation of STAG2 may cause CIN in patients with MM. To determine the possible molecular mechanism of mutational inactivation of STAG2 causing the CIN in MM, and the pathogenesis of MM, we will construct eukaryotic vector with wild STAG2 to transfect MM cell lines with STAG2 mutation, at same time, we will construct AAV vector to knock the novel mutation of STAG2 in MM cell lines without STAG2 mutation and we will study the effect of STAG2 mutation on the cohesin complex through co-immunoprecipitation (IP) and identify the effects of STAG2 mutation on the sister chromatid cohesion in prometaphase and on the anaphase integrity. This study will shed a light and a new drug target on the treatment of MM.