高嗜酸性粒细胞综合征患者粒细胞JAK/STAT信号转导途径的激活及对甲磺酸伊马替尼的治疗反应  

The activation of JAK/STAT signal pathway in hypereosinophilic syndrome and the patients therapeutic response to imatinib

作　　者：李斌[1] 张广森[1] 戴崇文[1] 裴敏飞[1] 

机构地区：[1]中南大学湘雅二医院血液科分子血液病研究室,长沙410011

出　　处：《中华医学杂志》2005年第7期448-452,共5页National Medical Journal of China

基　　金：美国CMB基金资助项目(NO99698)

摘　　要：目的确定高嗜酸性粒细胞综合征(HES)是否存在Janus酪氨酸激酶/信号传导与转录激活因子(JAK/STAT)信号途径的激活;进一步揭示HES的发病机制,并动态观察1例HES患者对甲磺酸伊马替尼(格列卫)治疗的临床反应及JAK/STAT蛋白质和FIP1L1 PDGFRA融合基因的变化。方法用Western印迹技术检测4例HES患者(3例FIP1L1 PDGRA阳性, 1例阴性),患者粒细胞中JAK2、STAT3及磷酸化STAT5(P STAT5)蛋白质表达水平;对1例FIP1L1 PDGFRA融合基因阳性的HES患者口服小剂量格列卫治疗,用逆转录(RT) 筑巢聚合酶链反应(PCR)及Western印迹技术动态检测格列卫治疗前、治疗后10、30、60d患者粒细胞的FIP1L1 PDGFRA融合基因及JAK2、STAT3、STAT5及P STAT5的表达。结果FIP1L1 PDGFRA融合基因阳性的3例HES患者均有JAK2,STAT3及P STAT5蛋白质表达的显著上调;而1例FIP1L1 PDGFRA阴性的HES患者上述蛋白表达几乎阴性。其中1例FIP1L1 PDGFRA( +)的HES患者服用小剂量格列卫治疗后,达到持续性血液学缓解(血象及嗜酸性粒细胞比例恢复正常,症状体征消失);服药30d后FIP1L1 PDGFRA融合基因的表达量明显减低, 60d后融合基因表达阴性;JAK2、STAT3、STAT5及P STAT5蛋白质表达呈时间依赖性下调, 60d后表达均阴性。结论HES患者粒细胞存在JAK/STAT信号途径的过?Objective To determine whether JAK/STAT pathway is involved in proliferation of hypereosinophilic syndrome (HES) cells, and reveal the pathogenesis of HES; observe the dynamic change of the clinical phenotype and hematological response, the expression of janaus kinase/ signal transducer and activator of transcription (JAK/STAT) protein or FIP1L1-PDGFRA mRNA in one HES patient treated with low-dose imatinib. Methods The granulocytes of peripheral blood of 4 HES patients, including 3 FIP1L1-PDGFRA positive cases and 1 negative case, were collected. The expression of JAK2, STAT3, and phosphorylated STAT (P-STAT5) proteins were detected by western blotting. One FIP1L1-PDGFRA fusion gene positive patient was administered with low-dose imatinib. Retrospective reverse transcription polymerase chain reaction (RT-PCR) analysis of FIP1L1-PDGFRA was performed and the expressions of JAK2, STAT3 and P-STAT5 were detected by western blotting before treatment and 10, 30, and 60 days after the beginning of treatment. Results Upregulation of JAK2, STAT3, and P-STAT5 proteins was shown in 3 FIP1L1-PDGFRA fusion gene positive HES patients, while all of these proteins were not expressed in one case of FIP1L1-PDGFRA negative HES. Continuous hematological remission was observed in one FIP1L1-PDGFRA fusion gene positive HES patient after low-dose imatinib treatment. The amount of FIP1L1-PDGFRA transcripts in peripheral blood granulocytes was significantly decreased in 30 days after therapy and turned negative 60 days after therapy. JAK2, STAT3, STAT5, and P-STAT5 expressions were all down-regulated time-dependently and were all negative 60 days after. Conclusion There is excessive activation of JAK/STAT signal pathway in HES patient, which may contribute to the malignant proliferation of eosinophils. Low-dose imatinib, that induces complete hematological and molecular genetic remission, exerts significant effects on FIP1L1-PDGFRA positive HES.

关 键 词：HES 患者 格列卫 融合基因 治疗 阴性 STAT3 信号途径 蛋白质表达 信号转导途径 

分 类 号：R55[医药卫生—血液循环系统疾病]