AKT/ROS信号通路对急性髓细胞白血病增殖的影响及靶向作用研究

项目名称： AKT/ROS信号通路对急性髓细胞白血病增殖的影响及靶向作用研究

项目编号： No.81200357

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 韩丽娜

作者单位： 哈尔滨医科大学

项目金额： 23万元

中文摘要： AKT信号通路及细胞内活性氧（ROS）高水平表达于急性髓细胞白血病（AML），研究发现二者之间存在相互作用，促进AML发生和白血病细胞增殖。我们前期的研究证实了ROS在维持正常干细胞功能中发挥关键作用。预实验发现在AML白血病干细胞（LSC）中，ROS表达水平高于正常干细胞。在持续表达AKT信号通路的K562白血病细胞系中，抗氧化剂NAC能够下调ROS表达，抑制细胞增殖。为了揭示AKT/ROS信号通路在AML中的靶向作用，本项目拟在已有研究基础上，联合应用AKT抑制剂AKTi-1/2和抗氧化剂NAC处理细胞，通过多参数流式细胞分析，细胞增殖，克隆形成试验等方法，分析AKT/ROS信号通路在白血病干细胞和祖细胞群中的表达水平，探讨靶向作用AKT/ROS信号通路对AML增殖的影响及ROS增加的相关机制。本项目可为AML靶向治疗提供理论和实践依据，有利于进一步改善AML疗效。

中文关键词： 急性髓细胞白血病；AKT 信号通路；活性氧；增殖；靶向作用

英文摘要： AKT signal transduction pathway is constitutively activated and cellular reactive oxygen species (ROS) are highly expressed in acute myeloid leukemia (AML) blasts, correlated with an unfavorable prognosis in this disease. It has been demonstrated in recent studies that a positive interplay existed between ROS and AKT signaling pathways in leukemia, conferring to development of leukemia and promoting proliferation of AML blasts. Our previous published data indicated that ROS was required in maintaining normal hematopoietic stem cell (HSC) pool. In our pilot study, intracellular ROS level was identified to be higher in AML leukemic stem cells (LSC) than in normal counterpart. Antioxidant NAC resulted in reduction of cellular ROS level, coincided with inhibition of proliferation in K562 leukemic cell line that overexpressed BCR-ABL-driven AKT signaling transduction pathway. In order to target AKT/ROS signaling transduction pathways in AML, AKT inhibitor (AKTi-1/2) in combination with antioxidant NAC will be applied in AML blasts on the basis of our previous data. By performing multiparametric intracellular flow cytometry, cell proliferation assay and colony-forming cells assay, we will analyze AKT/ROS expression in dissected AML LSC and progenitor cell fractions, investigate the inhibitory effect of AKTi-1/2 with N

英文关键词： acute myeloid leukemia；AKT signaling；reactive oxygen species；proliferation；targeting