蛋白酶体抑制剂(PIs)硼替佐米(BTZ)在多发性骨髓瘤(MM)中的耐药机制尚不清楚,文献报道骨髓微环境中的间充质干细胞(MSCs)对骨髓瘤耐药至关重要。我们发现BTZ耐药患者的骨髓MSCs分泌的外泌体(exosome)可以降低骨髓瘤细胞对PIs的药物敏感性，并且通过RNA-seq筛选出MSCs的exosome中新的转录本lncRNA-18626在BTZ耐药患者中的表达较其在BTZ敏感患者中的表达显著上调，从而提示骨髓MSCs的exosome介导的lncRNA-18626的转移可能在MM蛋白酶体抑制剂耐药中发挥重要作用。本课题拟在此基础上，在细胞和动物模型水平，确证lncRNA-18626在BTZ耐药中的作用；在分子水平，明确exosome中lncRNA-18626在骨髓瘤细胞中的作用靶点，从而揭示骨髓MSCs源exosome lncRNA-18626在骨髓瘤PIs耐药中的作用的分子机制。

Whereas the therapeutic benefit of proteasome inhibitors (PIs) remains unchallenged, acquired drug resistance remains a major obstacle toward achieving sustained clinical responses. We found that exosomes obtained from multiple myeloma (MM) patient bone marrow (BM) mesenchymal stromal cells (MSCs) promoted bortezomib resistance of human MM cells. We then identified lncRNAs differentially expressed in PIs-resistant MM BM-MSCs-derived exosomes by RNA-seq. MM BM-MSC-derived exosomes had a higher level of a novel lncRNA, lncRNA-18626 compared with PIs-sensitive MM BM-MSCs-derived exosomes. Therefore, we hypothesized that lncRNA-18626 present in the exosomes may mediate epigenetic transfer from the BM-MSCs to the MM tumor clone to enhance PIs resistance of MM cells. These in vitro and in vivo studies will demonstrate that a unique role of exosomal lncRNA-18626 in the cross-talk between BM-MSCs and MM cells in the resistance to PIs through exosomes. The goals of this study are to assess how exosomal lncRNA-18626 is involved in the PIs resistance of MM cells and through which molecular mechanisms it elicits this function.