EphB4/ephrinB2通过参与细胞骨架蛋白导致慢性髓性白血病对伊马替尼耐药。
EphB4/ephrinB2 Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Involved in Cytoskeletal Proteins.
作者信息
Li Lin, Xu Na, Zhang Jin-Fang, Xu Lu-Lu, Zhou Xuan, Huang Bin-Tao, Li Yu-Ling, Liu Xiao-Li
机构信息
1. Department of Hematology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou 510515, Guangdong, China.
2. Department of Paediatric Hematology and Oncology, Clinical Center of Tumor Therapy, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 510000, China.
出版信息
Int J Med Sci. 2016 Apr 28;13(5):365-73. doi: 10.7150/ijms.14989. eCollection 2016.
INTRODUCTION
The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown.
METHODS
The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models.
RESULTS
The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42.
CONCLUSION
Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins.
引言
EphB4/ephrinB2在慢性粒细胞白血病对伊马替尼耐药中的机制尚不清楚。
方法
建立伊马替尼耐药的慢性粒细胞白血病细胞系-K562-R。检测患者及耐药细胞中EphB4受体的表达。在EphB4基因敲低的细胞和小鼠模型中测试细胞迁移和药物敏感性。
结果
与慢性期患者相比，急变期患者中EphB4受体过度表达。EphB4受体表达水平与12个月内的完全细胞遗传学反应相关。在K562-R细胞中检测到EphB4受体表达增强。EphB4基因敲低在体外和体内均抑制细胞迁移能力并恢复对伊马替尼的敏感性。在K562-R细胞中观察到对伊马替尼的敏感性恢复，同时磷酸化EphB4水平升高，RhoA、Rac1和Cdc42的磷酸化水平降低。
结论
我们的研究表明，EphB4/ephrinB2的异常激活可能介导慢性髓性白血病对涉及细胞骨架蛋白的耐药。
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