细胞外基质蛋白Cyr61在慢性粒细胞白血病伊马替尼耐药中的作用及机制研究

Imatinib (IM) resistance is a key issue in treatment of chronic myeloid leukemia (CML). As a secreted extracellular matrix protein, Cyr61 is involved in chemotherapy resistance of solid tumors. However, the role of Cyr61 in IM resistance is unclear. Our preliminary data showed that the level of Cyr61 is obviously increased in CML patients with IM resistance, and down-regulating the Cyr61 expression of K562G cells (IM resistance to CML cell line K562) can improve sensitivity to the IM, but its mechanism remains to be further discussed. So we hypothesized that Cyr61 is involved in IM resistance by regulating apoptosis related proteins and/or the expression of drug transporters. Thus, we firstly aim to detect Cyr61 concentration in bone marrow from CML patients, then, using K562 cell line, primary CML cell and animal model of CML, explore the role and underlying mechanism of Cyr61 in IM resistance in CML from the molecules, cells and animal aspects. This study will contribute to illuminate the role and mechanism of bone marrow microenvironment in chemoresistance against tyrosine kinase inhibitors, which provide new ideas and promising strategies for the treatment of CML.

伊马替尼（IM）耐药是慢性粒细胞白血病（CML）临床治疗的主要问题。细胞外基质蛋白Cyr61参与多种肿瘤的耐药过程，但其在CML IM耐药中的作用及机制尚未见报道。我们的预实验结果提示Cyr61在CML IM耐药患者骨髓中含量明显增高，且下调K562G细胞（耐IM CML细胞系K562）Cyr61的表达能提高对IM的敏感性，但其作用机制有待进一步探讨。为此，我们提出假说：Cyr61可能通过调节凋亡相关蛋白和/或药物转运蛋白的表达，介导CML IM耐药。为了验证这一假说，我们在明确Cyr61在CML IM耐药患者骨髓中高表达基础上，通过K562G细胞、K562细胞、原代CML细胞和小鼠CML动物模型，从分子、细胞以及动物整体水平等多方面深入探讨Cyr61在CML IM耐药中的作用和机制。研究结果有望阐明白血病骨髓微环境在酪氨酸激酶抑制剂耐药中的作用及机制，为CML的治疗提供新的思路和策略。

伊马替尼（IM）耐药是慢性粒细胞白血病（CML）临床治疗的主要问题。细胞外基质蛋白Cyr61参与多种肿瘤的耐药过程。本课题研究发现，Cyr61在CML患者样本中骨髓、血浆及细胞系中表达增加，同时，还发现Cyr61在耐IM患者和细胞系K562G细胞中的表达水平增高。特异下调Cyr61的表达降低了K562G细胞对IM的耐药性，促进IM诱导的细胞凋亡；上调Cyr61的表达提高K562细胞对IM的耐药性，降低IM诱导的细胞凋亡；在CML小鼠模型中，特异下调Cyr61的表达能够提高K562G细胞对IM的化疗敏感性。这些结果说明，Cyr61在CML患者中增高且能够诱导CML细胞IM耐药。机制研究显示，Cyr61介导CML细胞IM耐药可能与ERK1/2通路促进ABC转运蛋白ABCG2和凋亡相关分子Bcl-xl的表达有关。本研究从骨髓微环境中的细胞外基质蛋白Cyr61入手为揭示CML IM耐药机制奠定基础，有助于我们对白血病发展过程中出现的难治复发和耐药等病理现象的机制产生新的认识，为难治性CML治疗提供新的策略。