Role of BCL6 Mutation in Lymphomagenesis

BCL6 突变在淋巴瘤发生中的作用

• 批准号: 6766053
• 负责人: Riccardo Dalla-Favera
• 金额: $ 33.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-05 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766053
• 关键词: B lymphocyte; CD40 molecule; alleles; biological signal transduction; cell cycle; cell line; chromosome aberrations; gene expression; gene mutation; genetic models; genetically modified animals; human tissue; interleukin 4; laboratory mouse; neoplasm /cancer genetics; neoplastic growth; nonHodgkin' s lymphoma; pathologic process; polymerase chain reaction; protein structure; transcription factor; transfection

DESCRIPTION (provided by applicant): The Bcl6 gene encodes a zinc-finger transcription factor and is altered by chromosomal rearrangements in its 5' non-coding region in approximately 30% of diffuse large-cell lymphoma (DLCL). In addition, the 5' non-coding region of Bcl6 is targeted by somatic hypermutation in normal germinal center (GC) B cells and in GC-derived B cell non-Hodgkin lymphoma (B-NHL). The general goal of this project will be to investigate the role of Bcl6 hypermutation in B-NHL pathogenesis. In particular, the following specific lines of investigations will be pursued: 1) Functional consequences of Bcl6 hypermutation; we will investigate the role of Bcl6 mutations on the regulation of Bcl6 expression by determining whether mutations i) affect CD40-mediated Bcl6 downregulation; ii) induce an increased sensitivity to STAT6-mediated IL4 signaling; 2) Role of Bcl6 mutation in lymphomagenesis; transgenic mice carrying NHL-derived mutant Bcl6 alleles will be constructed and examined for the effects of mutations on i) B cell lineage development, ii) tumor development; 3) Examine the role of germinal centers and IgV somatic hypermutation in lymphomagenesis; we will attempt to determine whether the presence of germinal center and/or somatic hypermutation are required for lymphomagenesis using a transgenic mouse model generated by crossing lymphoma prone mice (lambda-myc) with mice that are unable to either form GC (Bcl6delta/delta mice) or undergo somatic hypermutation (AID-/- mice).

描述（由申请人提供）：Bcl6基因编码锌指转录因子，并在其5'非编码区域中的染色体重排改变，大约30％的弥漫性大细胞淋巴瘤（DLCL）。此外，BCl6的5'非编码区域是正常生发中心（GC）B细胞中的体细胞过度靶向以及GC衍生的B细胞非霍奇金淋巴瘤（B-NHL）的靶向。该项目的一般目标是研究Bcl6超突变在B-NHL发病机理中的作用。特别是，将采用以下具体调查措施： 1）Bcl6超成名的功能后果；我们将通过确定突变i是否影响CD40介导的Bcl6下调来研究BCl6突变对BCL6表达调节的作用； ii）诱导对STAT6介导的IL4信号的敏感性提高； 2）Bcl6突变在淋巴作用中的作用；携带NHL衍生突变体Bcl6等位基因的转基因小鼠将被构造并检查突变对I）B细胞谱系发育的影响，ii）肿瘤发育； 3）检查生发中心和IGV躯体过性超数在淋巴作用中的作用；我们将尝试确定使用通过越过容易发生小鼠（Lambda-Myc）与无法形成GC（Bcl6delta/delta小鼠）或较不成想的体细胞超含量的小鼠产生的转基因小鼠模型（LAMBDA-MYC）生成的转基因小鼠模型是否需要生发中心和/或体细胞过度突破。