IDH突变肿瘤代谢物二羟基戊二酸致MDS向AML转化的机制研究

项目名称： IDH突变肿瘤代谢物二羟基戊二酸致MDS向AML转化的机制研究

项目编号： No.81470290

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： 佟红艳

作者单位： 浙江大学

项目金额： 70万元

中文摘要： 异柠檬酸脱氢酶（IDH）突变是髓细胞肿瘤的一个重要分子事件，IDH突变致肿瘤代谢产物二羟基戊二酸（2-HG）大量合成，以2-HG为核心的调控机制是IDH突变参与肿瘤发生的主要机制。骨髓增生异常综合征（MDS）具有向急性髓细胞白血病（AML）转化的特征，前期研究发现，MDS转化的AML中IDH突变较低危组MDS更为普遍，且存在与AML转化相关的低氧信号通路异常激活。本项目利用磁珠分选、Westernblot、基因测序、气相色谱质谱联用仪、慢病毒转染等技术，通过对大样本MDS骨髓标本IDH突变的检测及血清中2-HG含量的分析，并研究MDS细胞中2-HG如何通过影响α-KG依赖双加氧酶TET2、KDM及PHD对基因组DNA、组蛋白的甲基化以及低氧信号通路的调控作用，以此阐明IDH突变及其产生的肿瘤代谢产物2-HG参与MDS向AML转化的机制，为以IDH突变和2-HG为靶点的靶向治疗提供重要依据。

中文关键词： 基因突变；甲基化；骨髓增生异常综合征；异柠檬酸脱氢酶；二羟基戊二酸

英文摘要： Somatic mutation in the isocitrate dehydrogenase (IDH) genes plays a vital role in myeloid neoplasms. Mutant genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG), which is considered as the key effector of regulatory mechanism for contributing to tumorigenesis. Myelodysplastic syndromes (MDS) are a diverse group of clonal diseases derived from hematopoietic stem cells characterized by substantial risk for progression into acute myeloid leukemia (AML).In our previous studies,IDH mutations occurred at higher frequency in patients with AML which transform from MDS compared to those in low-risk MDS and the pathway of hypoxia-inducible factor 1 (HIF-1) was abnormally activated in high-risk MDS. We will use a series of new methods including magnetic activated cell sorting, gene sequencing technique, western blot, gas chromatography time of flight mass spectrometry, lentiviral transfection technique in this project,to assess the prevalence of IDH gene mutaions and the level of serum 2-HG in MDS. In the further research, to explore how 2-HG induces the disorganized state of deoxyribonucleic acid (DNA) methylated profile and the inhibition of histone demethylation according to repressing the function of ten-eleven translocation 2 (TET2) and histone lysine demethylases subfamily (KDMs), which are the α-ketoglutarate (α-KG) dependent dioxygenases.In addition, we will investigate the underlying principle whether 2-HG interrupt another α-KG dependent dioxygenase,prolylhydroxylases (PHD),to bring about the disorder of hypoxia-inducible factor 1 pathway and the accumulation of HIF-1 α in MDS.Identifying the potential molecular mechanism of IDH gene mutations and its oncometabolite 2-HG triggering MDS clone transforming to AML clone will be significant for providing the theoretical basis of a new and clinical promsing target in the treatment of MDS.

英文关键词： gene mutations;methylation;myelodysplastic syndromes;isocitrate dehydrogenase;2-hydroxyglutarate