激活突变SHP2（PTPN11）磷酸酶对白血病细胞恶性生物学行为的影响及分子机制探讨

项目名称： 激活突变SHP2（PTPN11）磷酸酶对白血病细胞恶性生物学行为的影响及分子机制探讨

项目编号： No.30873046

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 生物科学

项目作者： 汪思应

作者单位： 安徽医科大学

项目金额： 30万元

中文摘要： 白血病是儿童最常见的恶性肿瘤。患者常因白血病细胞易侵袭转移、耐药或高增殖性等恶性生物学行为特征而出现复发和转移，使治疗失败。目前人们对其机制了解不够。临床研究提示：某些基因突变可能与白血病细胞这些恶性生物学行为有关。我们前期研究发现：白血病发病相关癌基因SHP2的激活突变（磷酸酶活性升高），促进小鼠白血病的发病；高表达或生理水平表达激活突变SHP2的小鼠血细胞，其粘附迁移、对DNA损伤的抵抗能力及增殖敏感性较对照明显增强，提示激活突变的SHP2可能是调控白血病细胞恶性生物学行为的关键分子之一。为深入研究激活突变SHP2对白血病细胞的影响，我们建立了2株（WT，SHP2D16G/+）小鼠T细胞白血病瘤株，同时建立了人类肝癌和乳腺癌D61G突变SHP-2稳定高表达细胞株，发现不论是表达生理水平或高水平突变SHP-2的肿瘤，其恶性生物学行为如侵袭、增殖、耐药性比对照组细胞明显增强，其中可能与增强的MAPK、PI3K信号转导途径有关；SHP-2D61G突变增加了重金属污染物诱发致瘤突变敏感性；高表达突变SHP-2的肿瘤细胞群体中，其肿瘤干细胞比例明显增加，该课题为白血病防治提供新线索。

中文关键词： 白血病;SHP-2;基因突变;肿瘤

英文摘要： Leukemia is the most frequent malignant tumor in children. It often recurs or metastasizes because of invasion, drug resistance and hyper-proliferation of leukemic cells, which leading to treatment failure in these pediatric patients. The mechanisms still remains unclear. Some clinical investigations showed that mutation of some genes might be related with these malignant biological behaviors. Our previous studies have provided evidence that gain-of-function mutation (leading to hyper-activation of phosphatase) of a leukemia related oncogene Shp2 is involved in leukemogenesis. Over expression of Shp2 or knock-in gain-of-function mutant Shp2 in physiological level in mice blood cells resulted in enhanced abilities of cell adhere and migration, resistance to DNA-damage and sensitivity of proliferation compared with control group. These results indicated that gain-of-function mutant Shp2 might be one of the most important key molecules that regulated malignant biological behaviors of leukemic cells. In order to have a deeply study of Shp2's effect on leukemic cell, we have established two mice T cell leukemic cell pools (WT and SHP2D16G/+) and solid tumor with stable overexpress mutant SHP-2. Then found that tumor cell with mutant SHP-2 (physiological or overexpress level) got more malignant behivior including more easy to adhere and migration, more resistance to DNA-damage and proliferation faster than the tumor cell with normal Shp2. the molecular machnism may be related with enhanced MAPK and PI3K signal pathway induced by D61G mutant SHP-2. Activated mutant SHP-2 increased the risk of tumorigenesis induced by heavy metal contaminations. The cancer stem cell population were dramatically increased in the tumor cell with mutant SHP-2. Our study will provide some new methods for clinical treatments of leukemia.

英文关键词： Leukemia; SHP-2; Gene mutation; tumor