Although major advances have been achieved in the treatment of chronic myeloid leukemia (CML) by using tyrosine kinase inhibitors, patients relapse after withdrawal and need long-term medication. This reflects the CML clones have not been eliminated completely. The precise mechanisms for the maintenance of CML cells are not yet fully understood. The bone marrow microenvironment constitutes the sanctuary for leukemic cells. Mesenchymal stem cells (MSC) are an important component of the bone marrow microenvironment (BM). It plays an important role in the development and drug resistance of CML. Accumulating evidence indicates that exosomes play a vital role in cell-to-cell communication. We successfully isolated and purified exosomes from human bone marrow microenvironment-derived mesenchymal stem cells (hBMMSC-Exo) by serial centrifugation. In the present study, we investigated the effect of hBMMSC-Exo on the proliferation, apoptosis, and drug resistance of CML cells. The results demonstrated that hBMMSC-Exo had the ability to inhibit the proliferation of CML cells in vitro via miR-15a and arrest cell cycle in the G0/G1 phase. However, the results obtained from BALB/c nu/nu mice studies apparently contradicted the in vitro results. In fact, hBMMSC-Exo increased tumor incidence and promoted tumor growth in vivo. Further study showed the antiapoptotic protein Bcl-2 expression increased, whereas the Caspase3 expression decreased. Moreover, the in vivo study in the xenograft tumor model showed that hBMMSC-Exo promoted the proliferation and decreased the sensitivity of CML cells to tyrosine kinase inhibitors, resulting in drug resistance. These results demonstrated that hBMMSC-Exo supported the maintenance of CML cells and drug resistance in BM by cell-extrinsic protective mechanisms. They also suggested that hBMMSC-Exo might be a potential target to overcome the microenvironment-mediated drug resistance.

中文翻译：

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来自骨髓微环境的间充质干细胞的外来体影响CML细胞生长并促进对酪氨酸激酶抑制剂的耐药性

尽管通过使用酪氨酸激酶抑制剂在慢性粒细胞白血病（CML）的治疗方面取得了重大进展，但患者停药后会复发，需要长期服药。这反映出CML克隆尚未完全消除。维护CML细胞的精确机制尚未完全了解。骨髓微环境构成了白血病细胞的庇护所。间充质干细胞（MSC）是骨髓微环境（BM）的重要组成部分。它在CML的发展和耐药性中起重要作用。越来越多的证据表明，外泌体在细胞间的通讯中起着至关重要的作用。我们通过连续离心从人骨髓微环境来源的间充质干细胞（hBMMSC-Exo）中成功分离和纯化了外泌体。在本研究中，我们研究了hBMMSC-Exo对CML细胞增殖，凋亡和耐药性的影响。结果表明，hBMMSC-Exo具有通过miR-15a抑制体外CML细胞增殖并将细胞周期阻滞在G0 / G1期的能力。但是，从BALB / c nu / nu小鼠研究中获得的结果显然与体外结果相矛盾。实际上，hBMMSC-Exo增加了体内肿瘤的发生率并促进了肿瘤的生长。进一步的研究表明抗凋亡蛋白Bcl-2表达增加，而Caspase3表达减少。而且，在异种移植肿瘤模型中的体内研究表明，hBMMSC-Exo促进了CML细胞对酪氨酸激酶抑制剂的增殖并降低了其敏感性，从而导致了耐药性。这些结果表明，hBMMSC-Exo通过细胞外源性保护机制支持CML细胞的维持和BM中的耐药性。他们还建议，hBMMSC-Exo可能是克服微环境介导的耐药性的潜在目标。