FOXM1引发多发性骨髓瘤耐药性研究

Multiple myeloma (MM), the second most common hematologic malignancy, is a genetically heterogeneous disease. Patients with MM typically respond to initial treatment, but a majority will ultimately relapse. To pursue a pervasive cure for MM, identifying and addressing the drug-resistant MM subclones as well as garnering a better understanding of the genetic makeup of these subclones is required. Using global gene expression profiling (GEP), our group discovered that FOXM1 increased in MM cells compared to normal plasma cells. In addition, MM patients with high FOXM1 expression suffer poor survival relative to low-FOXM1 expressing patients. More importantly, we found that FOXM1 overexpressing MM cells were resistant to clinical chemotherapy drugs, Bortezomib and Doxorubicin et al. In this study, firstly we will validate the role of FOXM1 in drug-resistance in vitro by using lentiviral overexpressing and knockdown, RT-PCR , comparative genome hybridization and fluorescence in situ hybridization et al. on MM drug-resistance cell lines. Secondly, we will confirm the role of FOXM1-mediated MM drug-resistance in vivo through xenograft mouse model and 5TGM1 MM mouse model. At last, we will explore the mechanism that FOXM1 activates NEK2 and AURKA in MM by Chromatin Immunoprecipitation assay and proteome research et al. Our study will provide a novel target for the treatment of drug-resistant multiple myeloma and dramatically improve patient outcomes.

多发性骨髓瘤（MM）是第二大血液系统恶性肿瘤，大部分MM患者病症在治疗初期获得完全缓解，但随后出现耐药性并复发而最终死于MM。因此，揭示MM耐药性分子机制是目前MM基础研究与临床治疗的重要目标。本人研究发现FOXM1基因在MM细胞中的表达明显高于正常浆细胞，高表达FOXM1的MM患者生存率明显低于低表达患者。更为重要的是，过表达FOXM1的MM细胞对临床化疗药物呈明显的耐药性。本课题将围绕FOXM1引发MM细胞耐药性这一问题，首先采用慢病毒过表达和敲减FOXM1技术，通过RT-PCR、比较基因组杂交和荧光原位杂交等手段在体外验证FOXM1引发MM耐药性的作用；其次，运用免疫缺陷小鼠及5TGM1骨髓瘤小鼠模型确认FOXM1在体内介导MM耐药性的功能；最后，通过染色质免疫共沉淀、测序及结合蛋白质组学等技术研究MM细胞中FOXM1通过激活NEK2和AURKA引起耐药性和染色体不稳定的作用机理。

多发性骨髓瘤（Multiple Myeloma, MM）是恶性浆细胞病中最常见的一种类型，是第二大血液系统恶性肿瘤，其发病率占血液系统恶性肿瘤病人总数的10%左右。大部分MM患者病症在治疗初期获得完全缓解，但是随后出现耐药性，并复发而最终死于MM。本项目通过分析发现FOXM1在复发性骨髓瘤病人中呈显著上调趋势，其过表达与病人的生存期缩短和骨髓瘤增殖密切相关。随后的研究表明，过表达FOXM1可以促进体内骨髓瘤细胞的增殖、耐药性和异种移植肿瘤的发生发展，而敲低FOXM1的表达则逆转其对骨髓瘤细胞的上述作用。进一步的机制研究发现FOXM1与CDK6和NEK2在骨髓瘤细胞中共表达，一定程度上对Rb/E2F轴和CIN发挥正向调控作用，从而影响多发性骨髓瘤的耐药性。本研究对多发性骨髓瘤临床诊断、治疗、预后均具有重要指导作用，FOXM1具有成为临床诊断标志物的可行性，相关靶向抑制剂具有临床用药开发的前景。