骨髓微环境在多发性骨髓瘤（MM）的疾病进展和MM细胞耐药过程中起着重要作用，但其相关的分子机制并不清楚。我们的预实验结果提示: 低氧环境和骨髓基质细胞（BMSCs）可上调MM细胞内c-Myc表达并减弱其对硼替佐米治疗的敏感性。对MM细胞行RNA测序分析，发现3个受低氧和BMSCs调控的，且与c-Myc密切相关的长链非编码RNA（lncRNAs）。在此基础上，本项目拟：1）研究候选lncRNAs对MM细胞耐药的影响，筛选出介导耐药的关键lncRNAs；2）寻找关键lncRNAs作用的靶标；3）解析关键lncRNAs对c-Myc等耐药通路的调控作用和具体机制。4）在原代MM标本中验证关键耐药机制，力求发现逆转MM细胞耐药的小分子化合物。本研究将明确微环境促MM耐药的分子机制，为改善MM的治疗和减少疾病复发提供新策略。

It is well known that the bone marrow microenvironment plays an important role in the disease progress and drug resistance of multiple myeloma (MM), but the specific mechanisms are unclear. We have found that the therapeutic effects of bortezomib were significantly weakened by hypoxia and bone marrow stromal cells (BMSCs) with c-Myc elevation in MM cells. Furthermore, by RNA sequencing, we have obtained 3 candidated long noncoding RNAs (lncRNAs) which are controlled by hypoxia and BMSCs, and closely related to c-Myc in MM cells. Therefore, we will conduct further studies in several aspects. Firstly, study the effects of candidated lncRNAs in drug resistance in MM, and further screen out the key lncRNAs. Secondly, search for the targets of key lncRNAs. Thirdly, explore the special mechanisms of key lncRNAs in the drug resistance-related pathways, such as c-Myc. Finally, prove the role of the key lncRNAs in primary MM samples, and find out the compound which can convert drug resistance of MM. In summary, our study will shed light on the role of bone marrow microenvironment and its mechanisms in drug resistance of MM, and provide the novel treatment strategy to improve response rate and reduce relapse.