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

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.

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。

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，30% 的病人会进一步发展成髓系白血病 （AML） 。我们近期的研究发现在人类的髓系白血病细胞系中EVI-1激活可引起miR-9启动子序列甲基化。同时，EVI-1活化与人类的AML细胞系中miR-9失活相关。我们进一步阐明了EVI-1激活可引起miR-9启动子序列甲基化的分子机制。同时证明了EVI-1激活导致的miR-9基因的下调，在介导了EVI1在髓系白血病细胞系中的重要功能。另外， 我们分析了miR-9 在血液红细胞的前期细胞的功能及分子机制。本项目不仅进一步阐明EVI1诱导MDS及AML新的发病机制，而且为该疾病的治疗提供可能的新靶点。