Calreticulin突变在JAK2 V617F阴性的骨髓增殖性肿瘤中的研究

缺乏JAK2 V617F突变的骨髓增殖性肿瘤（MPNs） 的诊断存在巨大挑战。国际上对内质网伴侣分子calreticulin(CALR)不同突变类型以及在MPNs中的功能还没有深入研究。我们在前期CALR突变的研究基础上拟对MPNs的CALR突变及功能进行进一步研究：（1）继续研究不同突变类型患者的临床特征及预后意义，分析细胞表面的CALR表达水平；（2）研究突变是否引起细胞内Ca2+分布及CALR蛋白在细胞内的定位变化；（3）通过研究在JAK-STAT信号通路相关细胞因子IL-3，IL-6，G-CSF和JAK激酶抑制剂AG490刺激后，信号通路上STAT3和STAT5活化水平是否发生变化，相关基因SOCS1，SOCS3和CALR表达水平的变化，希望能深入探讨CALR突变在MPNs致病机制中的作用，最终深入全面地展示MPNs的生物学特征，对其预后分析乃至靶向治疗提供丰富详尽的信息。

Diagnosis of patients with MPNs who do not have JAK2 V617F mutation remains a challenge.The endoplasmic reticulum chaperone calreticulin (CALR) of different mutation types and functions in MPNs are no in-depth studies which will be investigated in this research: (1) continue to study the difference of clinical and prognostics of patients with distinct CALR mutation types, analyze the level of CALR expression on cell surface;(2)find whether CALR mutations change the distribution of Ca2+ and expression of CALR protein in cells; (3) after cytokines IL-3, IL-6, G-CSF in the JAK-STAT signaling pathway and JAK kinase inhibitors AG490 stimulation, whether the activation level of STAT3 and STAT5 and the expression of SOCS1, SOCS3 and CALR will change. We hope we can thoroughly understand the role of CALR mutations in molecular mechanism of MPNs and provide a reference for other molecular pathogenesis of MPNs. We can demonstrate a comprehensive and in-depth landscape of MPNs biology, and provide important clues for clinical diagnosis, prognosis analysis and targeted therapy of MPNs.