Mouse models of age-associated monoclonal gammopathy

描述（由申请人提供）：未确定意义的单克隆γ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岁以上的成年人占1%，50岁以上的占2%，90岁以上的占20%。据报道，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征是经常（70%）涉及免疫球蛋白（Ig）基因的染色体易位，并确定了四个常见的复发位点：11q13、6p21、4p16和16q23。易位导致强大的Ig增强子在这些基因座（分别是cyclin D1、cyclin D3、FGFR3+MMSET和c-maf）附近的癌基因并置，导致它们在浆细胞中的异位和失调表达。使用间期FISH，在恶性前MGUS中以相似的频率检测到IgH易位。当它们存在时，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，由于IgH易位，癌基因的异位表达是这些克隆浆细胞扩增发展的第一步。我们建议研究在衰老小鼠中自发发生的MGUS，建立抗原特异性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出负责MGUS的细胞，并研究其表型或基因型的变化。我们将确定这些扩增是否具有相似的异位基因表达，数字染色体异常或免疫球蛋白基因易位的证据。我们将确定持续的抗原暴露在维持克隆的大尺寸中的作用。最后，我们建议创建Ig调控元件控制相关癌基因表达的转基因小鼠，模拟Ig易位的影响。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与MGUS和MM的发生和发展有关的其他事件的贡献。

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.