多发性骨髓瘤（MM）的发生发展及复发耐药机制极其复杂，涉及肿瘤起始细胞与克隆演变、复杂遗传学异常导致的多种信号通路异常、瘤细胞与骨髓微环境恶性循环式相互作用等。因此，针对某一方面或某一靶点的治疗难以取得理想的治疗效果。本项目基于这一MM治疗中存在的关键问题，提出针对MM发病和耐药复杂机制的多维度靶向干预策略这一科学假设。在我们前期工作积累基础上，以原代MM患者标本、MM细胞系和MM小鼠模型为研究对象，在MM起始细胞、疾病不同状态的MM细胞和MM骨髓微环境三个维度上，以影响MM染色体稳定性的关键基因NEK2和AURKA为主要靶分子, 深入探讨MM的发病与耐药机制和相应的靶向干预策略。研究结果将为多发性骨髓瘤的多维靶向治疗新策略提供实验和理论基础。

Multiple myeloma (MM) has complicated chromosome instability mechanisms of pathogenesis, drug resistance and relapse, which include multi-dimensional issues, such as tumor-initiating cells and clonal evolution, signaling pathways abnormalities caused by complex genetic alterations and the vicious circle of interactions between tumor cells and bone marrow microenvironment. Therefore, it’s difficult to get satisfactory curative effects only by targeting any one dimension. To solve these critical problems existing in the approach to cure multiple myeloma, we hypothesize the multidimensional target therapy strategies for multiple myeloma. Based on our previous work on myeloma, myeloma primary cells, MM cell lines and MM mice models will be used as research subjects. The present project aims to elucidate the mechanisms of its pathogenesis, drug resistance and related targeting intervening measures by two chromosome instability associated key genes: NEK2 and AURKA ,from 3 aspects including MM initiating cells (MIC) , myeloma cells in different stages and bone marrow microenvironment related to myeloma. Our results will provide an experimental and theoretical basis for myeloma therapy multidimensionally.