SHP-1靶向AKT调控白血病细胞化疗耐药的机制研究

耐药复发是急性髓系白血病（AML）的临床难题。蛋白质酪氨酸磷酸酶在肿瘤治疗中有重要作用，申请人前期发现磷酸酶Shp-1可调控造血干细胞静息期维持（JEM 2018），但在AML化疗耐药中的作用和调控机制尚不清楚。申请人预实验发现AML小鼠模型中敲除Shp-1或使用Shp-1抑制剂联合阿糖胞苷和阿霉素治疗后，可显著减少耐药白血病干细胞（LSC）数量，延长小鼠生存期。进一步发现敲除Shp-1导致AML细胞PI3K-AKT通路过度活化，LSC周期加快和化疗后凋亡增加。已知Akt低活化状态是维持LSC静息期和耐药的关键，因此申请人提出假说：抑制Shp-1会使LSC中Akt信号通路过度活化，进而增加LSC对化疗药物的敏感性。申请人将在前期工作基础上，深入研究Shp-1通过Akt调控LSC化疗敏感性的分子机制，并探索在人AML治疗中的作用，为新型磷酸酶靶向药在AML治疗中的应用提供理论基础和药物靶点。

Chemotherapy drug resistance is a difficult problem in clinical treatment of acute myeloid leukemia (AML). It is proved that protein tyrosine phosphatases play an important role in tumor targeted therapy. The applicant found that Shp-1 maintains hematopoietic stem cell self-renewal ability, and its role in regulation of leukemia chemotherapy drug resistance is still unclear. The applicant find that deletion of Shp-1 or Shp-1 inhibitor can decrease AML leukemia stem cell (LSC) numbers, and improve chemotherapy drug therapeutic effect in MLL-AF9 induced AML mouse model. Further researches show that deletion of Shp-1 in AML cells can increase PI3K-AKT pathway enrichment, and in vivo phosphorylated Akt is significantly increased in Shp-1 deletion AML cells. It is known that Akt activity is low in drug-resistant LSC, therefore the applicant hypothesizes that inhibition of Shp-1 will active Akt signaling pathway in LSC, and increase the sensitivity of LSC to chemotherapy drugs. Based on these data, the applicant will further underline the molecular mechanism of Shp-1 regulating Akt signaling pathway in affecting the sensitivity of AML LSC to chemotherapy drugs, and the new strategy of phosphatase-targeted drugs in treatment of AML.