基于外显子组测序的急性淋巴细胞白血病致病基因鉴定及相关机制研究

项目名称： 基于外显子组测序的急性淋巴细胞白血病致病基因鉴定及相关机制研究

项目编号： No.81200373

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： 刘元昉

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 急性淋巴细胞白血病（ALL）是淋巴细胞发育分化过程中单个淋巴祖细胞发生多步骤体细胞突变而形成的克隆性疾病，寻找致病性的基因突变对其发病机制的理解至关重要。利用高通量第二代测序平台，本课题组前期已完成12例儿童和成人B-ALL患者的外显子组测序工作，之后又利用现有的大规模ALL样本库进行扩大验证，结果发现多个在B-ALL中具有重现性体细胞突变且功能重要的基因，且对其在B-ALL发病机制中的作用，国内外尚无报道。此外，部分基因已完成400余例样本的验证并发现较高突变率。本项目拟进一步明确候选基因在B-ALL中的突变率，选择其中突变率较高者，对其在B-ALL发病机制中所起的作用进行功能研究，并分析其与患者临床异质性的关联。本项目的研究结果将进一步深化人们对B-ALL发病机制的认识，为该病提供新的预后判断指标，完善其预后分析体系，此外还可为相关药物研究提供可能的新型治疗靶点，从而推动临床诊治的进展

中文关键词： 急性淋巴细胞白血病；第二代测序；发病机制；融合基因；预后

英文摘要： Acute lymphoblastic leukemia is a clonal disease resulted from multi-step somatic mutations generated during the development and differentiation process in a single lymphoid progenitor cell. It is of great importance to find the driver mutations in understanding of leukemogenesis.Our group has completed exome sequencing on 12 pediatric and adult B-ALL patients using high-throughput next-generation sequencing platform and has verified the mutations in expanded sample size utilizing the existing large-scale ALL sample database.The exome sequencing identified several functionally important genes with recurring somatic mutations without reports worldwide of their roles in B-ALL leukemogenesis.For some of these genes, verification work has been completed in more than 400 samples and a high mutation frequency observed. This project intends to further determine the mutation frequencies of those candidate genes, and for those with higher frequencies of mutation, functional study will be conducted for their roles in leukemogenesis as well as their association with clinical heterogeneity. Our results will further deepen our understanding of the pathogenesis of ALL and recognize valuable new prognostic factors for clinical practice, also provide potential new therapeutic targets for related drug researches, thereby promoti

英文关键词： acute lymphoblastic leukemia；next-generation sequencing；leukemogenesis；fusion gene；prognosis