t（8；21）急性髓系白血病中甲基化沉默miR148/152及去甲基化特异性疗效的机制研究

项目名称： t（8；21）急性髓系白血病中甲基化沉默miR148/152及去甲基化特异性疗效的机制研究

项目编号： No.81470010

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： 于力

作者单位： 中国人民解放军总医院

项目金额： 80万元

中文摘要： t（8；21）AML是一种常见的白血病，易位产生的AML1-ETO（AE）融合蛋白在白血病的发生中起着重要的表观调控作用。AE融合蛋白的AML1可以与DNA相结合，ETO可募集DNMT1、HDAC及P300等蛋白分子形成复合体沉默抗癌基因或激活癌基因。miRNA是一类内源性非编码RNA，可以在转录或转录后水平调节基因的表达，在肿瘤发生中起着重要作用。我们研究组前期研究发现去甲基化药物对AE阳性白血病细胞的抑制作用明显高于AE阴性细胞，具有特异性疗效；miRNA 148/152在t(8;21)AML中被DNA甲基化沉默；同时还发现AML-ETO、c-KIT及DNMT1的3'UTR区均有该组miRNA的结合位点，可能直接参与上述重要癌基因的调控。本研究拟在应用去甲基化药物逆转miR148ab/152的甲基化沉默，恢复其对癌基因的抑制作用，并探讨其表观调控机理，为临床上去甲基化靶向治疗提供依据。

中文关键词： t(8;21)急性髓系白血病；DNA甲基化；去甲基化治疗；miRNA

英文摘要： patients habor the translocation of t（8；21）results in the formation of AML1-ETO fusion protein，which is the initial factor of t（8；21）acute myeloid leukemia. Epigenetic modifying enzymes recruited by AML1-ETO also plays a crucial role in the development of t（8；21）AML. HAT p300 involved in the upregulation of AE taget oncogenes such as c-kit and DNMT1；while DNMTs recruited by AE is an important repressive factor of lots of tumor suppressors targeted by AE.Preliminary studies suggest the promoter region of tumor suppressor miR148ab/152 revealed several AML1 binding site which locate in the CpG islands，which may be epigenetic silenced by DNMT1. Meanwhile, miR148ab/152 plays an important role in the post transcriptional regulation of oncogene c-kit and DNMT1. miR148ab/152 down-regulation leads to c-kit and DNMT1 overexpress, thus, maintaining the survival of leukemic stem cells , promote the malignance of leukemia.Demethylation treatment reverses the miR148ab/152 methylation silencing, restoring the expression of miR148ab/152, improve the sensitivity of t (8; 21) AML-specific demethylation therapeutic.This study will characterize the mechanism of how miR148ab/152 regulating the expression of those important oncogenes, and Improve the prognosis of the t(8;21) leukemia patients.

英文关键词： t(8;21) acute myeloid leukemia;DNA methylation;demethylation therapy;miRNA