急性白血病细胞中TSC2异常表达对mTORC1通路活性及白血病细胞生物学的影响

项目名称： 急性白血病细胞中TSC2异常表达对mTORC1通路活性及白血病细胞生物学的影响

项目编号： No.81200390

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： 徐智芳

作者单位： 山西医科大学

项目金额： 23万元

中文摘要： mTORC1信号通路在急性白血病（AL）细胞中常常被过度激活，其活化过程通过不同的上游信号机制调节，但最终聚焦于TSC1/TSC2复合体，其中，PI3K/AKT能够通过磷酸化抑制TSC2进而激活mTORC1。但是，在部分AL细胞中，mTORC1的活化是PI3K/AKT非依赖性的，其活化机制还不清楚。我们前期研究发现，TSC2基因在部分AL患者中表达降低，其启动子区的超甲基化是其表达下调的原因。由此提出假设：在AL细胞中，TSC2低表达与mTORC1的异常激活及白血病的发生有关。本项目将针对AL骨髓原始细胞并以正常人骨髓CD34阳性细胞为对照，联合siRNA技术，研究TSC2低表达对mTORC1通路激酶活性及白血病细胞生物学的影响；通过慢病毒表达系统研究过表达TSC2联合mTORC1抑制剂或去甲基化药物对AL的治疗作用，为进一步探索AL发病机制、开发个体化靶向治疗药物提供理论基础。

中文关键词： tsc2；mTOR；白血病；基因功能；信号通路

英文摘要： Recent studies have demonstrated that the mTORC1 pathway is aberrantly activated in blasts from acute leukemia (AL) patient and that mTOR inhibitors strongly inhibits the growth of the most immature AL cell lines. mTORC1 activation is regulated by different upstream mechanisms, mostly convergent on the TSC1/TSC2 complex. These include PI3K/AKT, which can activate mTORC1 by phosphorylating TSC2. Several studies have indicated that constitutive mTORC1 activation is PI3K-independent in AL and the mechanisms leading to constitutive mTORC1 activation in primary AL blast cells are currently unknown. Our previous study demonstrated that the reduced expression of TSC2 might be involved in the pathogenesis of leukemogenesis and hypermethylation of the TSC2 promoters are associated with the reduced expression. These data raise the question as to whether TSC2 genes deficiencies are related to the constitutively activation of mTOR and dysfunction of TSC2-mTORC1 pathway is involved in AL. This study will detect the expression of TSC2 in AL blast cells in control of normal bone marrow CD34 positive cells through real time PCR and western bolt to further validate the downregulation of TSC2 in AL；investigate the effect of mTOR kinase activity and leukemia cell biology for TSC2 via small interfering RNAs technology; explore the

英文关键词： tsc2；mTOR；leukemia；gene function；signal pathway