EVI1基因通过诱导表观遗传学改变导致骨髓增生异常综合征的分子机制

项目名称： EVI1基因通过诱导表观遗传学改变导致骨髓增生异常综合征的分子机制

项目编号： No.81470292

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： 钱志坚

作者单位： 同济大学

项目金额： 75万元

中文摘要： 表观遗传的改变是肿瘤进展的主要驱动因素。癌基因导致基因及微小RNA的表观遗传失调的分子机制仍未阐明。EVI1癌基因高表达促进血液系统恶性疾病骨髓增生异常综合征（MDS）的发生及发展。我们最近的研究发现髓系生成中miR-9扮演重要的角色，EVI1能通过异常的DNA甲基化导致miR-9的表达下调。已有报道miR-9的下调与癌症的发生相关。因此，我们认为EVI1诱导的miR-9表观遗传的改变破坏了造血干/祖细胞的功能，最终促进MDS的发生。本项目结合遗传学及生物化学手段，分析哪一个DNA甲基化转移酶在EVI1诱导的miR-9的异常甲基化中起关键作用。另外，我们通过各种嵌合体小鼠模型，研究miR-9在EVI1诱导MDS中的作用及阐明miR-9下游重要的信号通路。本项目不仅进一步阐明EVI1诱导MDS新的发病机制，而且为该疾病的治疗提供可能的新靶点。

中文关键词： 表观遗传学；DNA甲基化；骨髓增生异常综合征/；MDS；EVI-1；微小RNA-9

英文摘要： Epigenetic changes are major drivers of malignant progression. The molecular mechanism how an oncogene leads to an abnormal epigenetic regulation of genes and miRNAs expression is poorly understood. EVI1 is a well-known oncogene, and high expression of EVI1 contributes to the pathogenesis of MDS that is a hematological malignant disease. Recently, we found that miR-9 plays a key role in myelopoiesis and that EVI1 downregulates the expression of miR-9 by induction of DNA hypermethylation. Downregulation of miR-9 is associated with tumorigenesis.Therefore, we propose to test our hypothesis that EVI1-induced inappropriate epigenetic modifications of miR-9 disrupts the function of hematopoietic stem/progenitor cells, ultimately contributing to leukemogenesis. We will use genetic and biochemical approaches to determine which DNA methyltransferases plays a key role in EVI1-induced aberrant DNA methylation. In addition, we will use animal models to determine the role of miR-9 in EVI1-induced MDS and its key down-stream pathway. This study will elucidate a novel molecular mechanism by which EVI1 contributes to leukemogenesis, as well as a new role of miR-9 in EVI-induced leukemogensis. Finally, this study potentially leads to the identification of new therapeutic strategy for the treatment of EVI1-induced MDS.

英文关键词： epigenetic;DNA-methyla;Myelodysplastic Syndrome;EVI-1;microRNA-9