Mouse models of age-associated monoclonal gammopathy

年龄相关性单克隆丙种球蛋白病小鼠模型

• 批准号: 6895530
• 负责人: Peter Leif Bergsagel
• 金额: $ 31.28万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895530
• 关键词: B lymphocyte; aging; cell transformation; chromosome disorders; clone cells; cyclins; disease /disorder model; fluorescent in situ hybridization; gammopathy; gene expression; gene induction /repression; genetic regulatory element; genetically modified animals; genotype; immunoglobulin genes; immunoglobulins; laboratory mouse; model design /development; oncogenes; phenotype; plasma cells; polymerase chain reaction; transfection /expression vector

DESCRIPTION (provided by applicant): Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition and its frequency increases dramatically with age: 1% of adults over 25, 2% of those over 50, and 20% of those over 90. It is reported to progress to multiple myeloma (MM) at a rate of 1% per year. Recently we have shown that multiple myeloma is characterized by frequent (70%) chromosome translocations involving the immunoglobulin (Ig) genes and identified four recurrent loci that are commonly involved: 11q13, 6p21, 4p16, and 16q23. The translocations result in the juxtaposition of powerful Ig enhancers adjacent to oncogenes at these loci (cyclin D1, cyclin D3, FGFR3+MMSET, and c-maf, respectively), causing their ectopic and deregulated expression in plasma cells. Using interphase FISH, IgH translocations are detected with a similar frequency in the pre-malignant MGUS. When present, they are present in every clonal cell, indicating that the translocation event precedes the clonal expansion. We hypothesize that the ectopic expression of oncogenes, as a result of IgH translocation, is the first step in the development of these clonal plasma cell expansions. We propose to study MGUS that occurs spontaneously in aging mice, develop a murine model for the generation of antigen-specific MGUS, and study the B cell clones that produce them. Such a model will allow us to isolate the cells responsible for the MGUS and study alterations in their phenotype or genotype. We will determine if these expansions share similar ectopic gene expression, evidence of numerical chromosomal abnormalities, or immunoglobulin gene translocation. We will determine the role of ongoing antigen exposure in maintaining the clone's large size. Finally, we propose to create transgenic mice in which the expression of the relevant oncogenes is controlled by Ig regulatory elements, mimicking the effect of the Ig translocation. These studies will allow us to define the role of these genetic abnormalities in the development of plasma cell neoplasms. They also provide a framework to identify and study the contribution of additional events involved in the initiation and progression of MGUS and MM.

描述（由申请人提供）：不确定意义（MGU）的单克隆性伽马病是一种良性疾病，其频率随着年龄的增长而大大增加：25岁以上的成年人中有1％以上50％以上的成年人，其中20％以上的成年人，据报道以每年1％的速度发展为多发性骨髓瘤（MM）。 最近，我们表明多发性骨髓瘤的特征是涉及免疫球蛋白（IG）基因的频繁（70％）染色体易位，并鉴定出通常涉及的四个经常性基因座：11q13，6p21，4p16和16Q223。 易位导致在这些基因座（Cyclin D1，Cyclin D3，FGFR3+MMSET和C-MAF）相邻的强大IG增强子并并排，从而导致其在血浆细胞中的异位和导致表达。 使用相间的鱼类，在预防前MGU中以相似的频率检测到IGH易位。 在场时，它们存在于每个克隆细胞中，表明易位事件在克隆膨胀之前。 我们假设癌基因基因的异位表达是IGH易位的结果，是这些克隆浆细胞膨胀的发展的第一步。我们建议研究在老化小鼠中自发发生的MGU，开发出一种用于产生抗原特异性MGU的鼠模型，并研究产生它们的B细胞克隆。 这样的模型将使我们能够分离负责MGU的细胞并研究其表型或基因型中的改变。 我们将确定这些膨胀是否具有相似的异位基因表达，数字染色体异常的证据或免疫球蛋白基因易位。 我们将确定持续的抗原暴露在维持克隆大小中的作用。 最后，我们建议创建转基因小鼠，其中相关癌基因的表达受到IG调节元件的控制，从而模仿Ig易位的效果。 这些研究将使我们能够定义这些遗传异常在浆细胞肿瘤发展中的作用。他们还提供了一个框架来识别和研究MGU和MM启动和进展中涉及的其他事件的贡献。