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: 7227089
• 负责人: Peter Leif Bergsagel
• 金额: $ 29.66万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227089
• 关键词: 11q13; 4p16; 6p21; Adult; Age; Aging; Antigens; B-Lymphocytes; Benign; Cell Line; Cells; Chromosomal translocation; Chromosome abnormality; Clonal Expansion; Condition; Cyclin D1; Development; Ectopic Expression; Enhancers; Event; Frequencies; Gene Expression; Generations; Genes; Genetic; Genotype; Human; Human Development; Immunoglobulin Genes; Immunoglobulin Switch Recombination; Immunoglobulins; Incidence; Interphase; Kinetics; Modeling; Molecular; Molecular Abnormality; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Mutation; Numerical Chromosomal Abnormality; Oncogenes; Pathogenesis; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Premalignant; Principal Investigator; Rate; Recurrence; Regulatory Element; Reporting; Retroviral Vector; Role; Somatic Mutation; Splenocyte; Technology; Time; Transgenic Mice; Transgenic Organisms; Work; age effect; age related; cyclin D3; established cell line; man; mouse model; programs; size

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）：意义未明的单克隆丙种球蛋白病 (MGUS) 是一种良性疾病，其发病率随着年龄的增长而急剧增加：25 岁以上成年人中为 1%，50 岁以上成年人中为 2%，90 岁以上成年人中为 20%。据报道，其以每年 1% 的速度进展为多发性骨髓瘤 (MM)。 最近，我们发现多发性骨髓瘤的特点是频繁（70%）涉及免疫球蛋白（Ig）基因的染色体易位，并确定了四个经常涉及的复发位点：11q13、6p21、4p16 和 16q23。 这些易位导致强大的 Ig 增强子与这些位点（分别为细胞周期蛋白 D1、细胞周期蛋白 D3、FGFR3+MMSET 和 c-maf）的癌基因相邻，从而导致它们在浆细胞中的异位和失调表达。 使用间期 FISH，可以在恶变前 MGUS 中以相似的频率检测到 IgH 易位。 当存在时，它们存在于每个克隆细胞中，表明易位事件先于克隆扩增。 我们假设 IgH 易位导致的癌基因异位表达是这些克隆浆细胞扩增发展的第一步。我们建议研究衰老小鼠中自发发生的 MGUS，开发用于产生抗原特异性 MGUS 的小鼠模型，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 MGUS 的细胞并研究其表型或基因型的改变。 我们将确定这些扩展是否具有相似的异位基因表达、数值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尺寸方面的作用。 最后，我们建议创建转基因小鼠，其中相关癌基因的表达由 Ig 调控元件控制，模仿 Ig 易位的效果。 这些研究将使我们能够确定这些遗传异常在浆细胞肿瘤发展中的作用。它们还提供了一个框架来识别和研究涉及 MGUS 和 MM 的启动和进展的其他事件的贡献。