EZH2和MLL2基因突变在滤泡性淋巴瘤发生中的作用及分子机制

项目名称： EZH2和MLL2基因突变在滤泡性淋巴瘤发生中的作用及分子机制

项目编号： No.81472597

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： 郭双平

作者单位： 中国人民解放军第四军医大学

项目金额： 72万元

中文摘要： 滤泡性淋巴瘤是生发中心B淋巴细胞来源的一种常见恶性肿瘤，EZH2和MLL2分别催化组蛋白H3K27和H3K4甲基化，是一对调控生发中心B细胞正常发育的表观遗传学开关。文献和我们的研究表明，滤泡性淋巴瘤中存在EZH2功能获得性突变（7.2-30.7%）和MLL2功能缺失性突变（89%），30.7%滤泡性淋巴瘤同时有二者的突变，但EZH2和MLL2同时突变的生物学意义及其在滤泡性淋巴瘤发生中的作用及分子机制尚不清楚。我们对EZH2突变和野生型的滤泡性淋巴瘤基因表达谱分析，发现EZH2突变的滤泡性淋巴瘤，B淋巴细胞增殖、分化和凋亡基因异常表达。本课题拟在此基础上，深入研究EZH2和MLL2突变对生发中心B淋巴细胞发育的影响及分子机制；揭示EZH2和MLL2突变在滤泡性淋巴瘤发生中的作用和分子机制；阐明其在滤泡性淋巴瘤发生中的意义。本研究可发现滤泡性淋巴瘤发生的新机制，为分子靶向治疗提供理论依据。

中文关键词： C16_淋巴瘤；EZH2基因；MLL2基因；基因突变；组蛋白甲基化

英文摘要： Follicular lymphoma is a common subtype of B cell lymphoma derived from germinal center B cell, of which tumorigenesis is unclear at present. EZH2 and MLL2 belong to the histone 3(H3) methyltransferase, which catalyze the methylation of the lysine 27(K27）and 4(K4) residue of H3 respectively. Methylation of H3K27 is a repressive mark of gene expression, and methylation of H3K4 is an active mark on the contrary, which is the important epigenetic control playing important role in normal embryonic development and tissue differentiation. According to references and our study, EZH2 Y641 and MLL2 mutated in 7.2%-30.7% and 89% follicular lymphoma respectively,and 30.7% follicular lymphoma harboring EZH2 and MLL2 mutation simultaneously. It has been demonstrated that EZH2 Y641 mutation is gain-of-function, and MLL2 mutation is loss-of-function.We detected the frequency of EZH2 mutation in follicular lymphoma and analyzed the gene expression profiling of follicular lymphoma with or without EZH2 mutation.A group of significantly differential expression genes was found between the two cohorts.The function and significance of certain differentially expressed gene was studied, however,it is unclear about the biology significance of the histone methyltransferase EZH2 and MLL2 mutants in normal germinal center B cell development and malignant transformation.Simultaneous mutation of EZH2 and MLL2 probably result in the imbalance of the epegenetic control of gene expression in germinal center B cell development and enhance the tumorigenesis of follicular lymphoma.On the basis of our previous study, we are planning to deeply investigate the role of EZH2 and MLL2 mutation in the tumorigenesis of follicular lymphoma, the role of both mutants in controlling proliferation and differentiation of germinal center B lymphocytes. The project is expected to expand the study of epigenetic control of proliferation and differentiation of germinal center B lymphocytes, to explore the new mechanism of tumorigenesis of follicular lymphoma, and to provide the basis for specific rational combinatorial targeted therapy for follicular lymphoma.

英文关键词： lymphoma;EZH2 gene;MLL2 gene;gene mutation;histone methylation