谷氨酰胺转运蛋白ASCT2介导激活突变Ptpn11(SHP2)促进骨髓增殖性肿瘤的发生

Glutamine transporter ASCT2 mediates activation mutationPTPN11 (SHP2) to promote the occurrenceof myeloproliferative neoplasms

目的探索谷氨酰胺转运蛋白ASCT2对SHP2激活突变后致骨髓增殖性肿瘤(MPN)的影响,并且使用ASCT2抑制剂L-谷氨酰基-4-硝基苯胺(GPNA)观察其能否抑制MPN的发病进程。方法通过构建Ptpn11E76K/+Mx1-Cre+激活突变鼠MPN模型,分析正常小鼠和突变鼠细胞增殖能力、氨基酸及谷氨酸含量和细胞内糖酵解情况,对比ASCT2蛋白表达量和能量应激;使用GPNA处理小鼠,比较突变鼠和药物处理组ASCT2蛋白、能量应激通路中p-mTOR等蛋白表达量和对疾病发病的抑制情况。结果Ptpn11E76K/+Mx1-Cre+激活突变鼠谷氨酸及ASCT2蛋白表达量高,细胞增殖能力增强;抑制ASCT2蛋白功能后,MPN的发病进展受阻。结论ASCT2的表达量与SHP2激活突变后致MPN的发病进程相关,抑制ASCT2能够有效抑制SHP2激活突变所致骨髓增殖性肿瘤的发病进程,显示ASCT2可能是治疗该类型疾病的有效靶点。

Objective To explore the effect of glutamine transporter ASCT2 on myeloproliferative neoplasms(MPN)induced by SHP2 activation mutation, and to observe whether ASCT2 inhibitor l-glutamyl-4-nitroaniline(GPNA) can inhibit the progression of myeloproliferative neoplasms. Methods By constructing MPN mice model induced by Ptpn11E76 K/+ activated mutation, the cell proliferation ability, amino acid and glutamic acid content, intracellular glycolysis of normal mice and mutant mice were analyzed, and the expression of ASCT2 protein and energy stress were compared. The mice were treated with ASCT2 inhibitor(GPNA), and ASCT2 protein and energy stress were compared between mutant mice and treated groups. The expression of p-mTOR and related proteins in the energy stress pathway and the rescue effect of the disease were detected. Results Ptpn11E76 K/+ Mx1-Cre+ activated mutant mice had high expression of glutamic acid,ASCT2 protein and strong cell proliferation ability;ASCT2 inhibitor decreased the progression of myeloproliferative neoplasms. Conclusion The expression level of ASCT2 is closely related to the pathogenesis of myeloproliferative neoplasms induced by SHP2 activated mutation. Inhibition of ASCT2 can effectively decrease the morbidity of myeloproliferative neoplasms, suggesting that ASCT2 may be an effective target for treating this type of disease.