AMPK激动剂对人白血病细胞的抑制作用及机制研究

项目名称： AMPK激动剂对人白血病细胞的抑制作用及机制研究

项目编号： No.81470321

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 胡晓霞

作者单位： 中国人民解放军第二军医大学

项目金额： 75万元

中文摘要： 在前期工作中，我们发现伴有糖耐量异常的急性淋巴细胞白血病（ALL）患者无病生存期缩短，同时比对了白血病患者体内白血病干细胞和正常造血干细胞的AMPK表达情况，发现白血病干细胞AMPK磷酸化水平降低。而磷酸化AMPK/AMPK比值在白血病患者初发、复发时均降低，并与疾病的临床结局具有很强的相关性。进一步研究发现，AMPK激动剂二甲双胍不仅能控制血糖，还能提高AMPK磷酸化水平，并且有一定的抗肿瘤作用。结合临床研究结果，本项目拟进一步扩大病例研究，从mRNA表达水平、蛋白表达水平和细胞水平研究二甲双胍对白血病生物学特征的影响，以及AMPK磷酸化和白血病患者预后的关系；利用基因敲减及相应的功能实验，研究AMPK在白血病细胞中的确切功能；通过高通量检测方法、生物信息学和体内实验，明确二甲双胍调控白血病细胞生物学行为的方式，为AMPK激动剂及其作用通路成为白血病治疗靶点奠定实验基础。

中文关键词： 白血病干细胞；急性淋巴细胞白血病；信号通路；发病机制

英文摘要： The competition between leukemic and normal hematopoietic cells determines the outcome of leukemia patients. Leukemia cells and hematopoietic stem cells （HSCs）share the ability to self-renew; thus, the genes and pathways associated with maligancies often also regulate HSC function. Much efforts has gone into identifying genes that are differentially expressed in leukemia relative to HSCs. In previous study, we have defined the different expression pattern of AMP-activated protein kinase (AMPK) between leukemia stem cells and normal HSCs. The phosphorylation of AMPK was depressed in HSC isolated from patients with de novo and relaped leukemia, whereas, up-regulated in HSC of patients achieved complete remission. Moreover, its expression pattern is strongly associated with the prognosis of leukemia patients. Hyperglycemia, which is not uncommon during the treatment of acute lymphocytic leukemia (ALL), has been shown to be an independent predictor of adverse outcomes among hospitalized patients with undiagnosed diabetes; it also may have the potential to affect leukemic cell proliferation through altered metabolism. Metformin is an activator of AMPK which inhibits protein synthesis and gluconeogenesis during cellular stress. The biological function of metformin has been linked to the functions of AMPK, which has essential roles in DNA replication, repair and cell cycle control. In the present project,we will further identify the association between phosphorylation of AMPK and prognosis in a expanded case-control study. The specific function of AMPK agonist metformin in leukemic cells will be investigated through gene, protein, cell and on the whole. And the aberrant up-stream signal pathway regulated AMPK in de novo and relapsed leukemia will be investigated through the animal model. The results obtained from cell lines will be verified in humanized leukemia model and clinical samples. The project will specify the function and mechanism of aberrant phosphorylation of AMPK in human leukemia and provide evidences for metformin application in leukemia therapy.

英文关键词： leukemia stem cell;acute lymphoblastic leukemia;signal pathway;pathogenesis