利用iPS技术研究复发T-细胞急性淋巴细胞白血病（T-ALL）细胞亚克隆中基因变异特征及其耐药复发机制

项目名称： 利用iPS技术研究复发T-细胞急性淋巴细胞白血病（T-ALL）细胞亚克隆中基因变异特征及其耐药复发机制

项目编号： No.81470315

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： 李彦欣

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： T细胞急性淋巴细胞白血病(T-ALL)复发率高、预后差，是临床亟待解决的科学难题之一。一般认为白血病的耐药复发与白血病细胞的基因异质性有关，但目前缺乏系统性的研究。我们预实验测序结果表明，与初发T-ALL标本相比，5对复发标本中基因突变数量都显著增加，这给判断主导耐药基因突变造成困难。我们拟利用iPSC技术解决这一难题：一个iPS细胞系来自同一个细胞，不同的iPS细胞系之间的基因异质性代表同一标本亚克隆之间的差异；而且iPS细胞分化后又会重现白血病细胞的药物敏感性和疾病特征。本项目将在前期测序结果的基础上，建立同一标本的多个iPS细胞系，检测iPS细胞系内存在的与耐药可能相关基因突变；再将iPS细胞分为不同的亚克隆群，比较不同白血病亚克隆群之间的耐药性与基因突变的关系，从而找到主导T-ALL耐药的特异基因突变及相关分子机制，为阐明T-ALL的耐药复发机制提供全新研究策略和手段。

中文关键词： 儿童急性淋巴细胞白血病；白血病干细胞；耐药机制；化疗耐药；信号通路

英文摘要： Children T-ALL Leukemia is a blood cancer with the high rates of relapse (40-50%). Although stem cell heterogeneity and gene mutations in T-ALL leukemia are thought to be the main reasons of its drug resistance and relapse, the molecular mechanisms of T-ALL replase remain elusive. Our preliminary data showed that compared with the primary T-ALL sample, a lot of gene mutations were found in 5 pair relapse samples after genome sequencing.It is hard to dissolve which one mutation is the major important for T-ALL relapse. iPSC technology is helpful to solve this. In general,an iPS cell lines is generated from a single cell, a couple of different iPS cell lines derived from one patient sample can stand for the leukemia stem cell heterogeneity. Using these different iPS cells is easy to address the relative of stem cell heterogeneity and gene mutations with drug resistance and relapse. Our data published have showed that iPSCs derived from mouse leukemia cells have the full developmental ability as ES cell to generate chimeric and iPS mice, and these mice will be died within one month with leukemia, indicating that the iPS cells derived from the leukemia cells will re-develop leukemia. iPS cells and their derived-differentiation cells will be the good materials to study the mechanism of drug resistance and relapse in vitro and in vivo. In this proposal, we will use iPS technology to establish a number of different iPS Cell lines from the same T-ALL patient sample.This in vitro patient-derived stable and sensitive platform is useful to dissolve the cell heterogeneity with drug resistance and relapse. Combined with DNA-Seq technology, it is good way to elucidate gene mutations and drug resistance. Moreover,it is very helpful to design patient's personal targeted drug treatment.

英文关键词： T-ALL;leukemia stem cell;drug resistance and relapse;drug resistance;signaling pathway