Identification of Loci Modifying Atm Lymphomagenesis

 描述(申请人提供)：共济失调-毛细血管扩张症(A-T)是一种遗传性综合征，与白血病和淋巴瘤的高风险相关。这种综合征出现在atm基因有两个缺陷副本的个体中，但特定的A-T患者是否会患上白血病或淋巴瘤似乎不是由他们的atm突变(S)控制的，而是由未知的修饰基因控制的。在ATM基因敲除的A-T小鼠模型中，淋巴瘤的发病率和潜伏期取决于携带ATM基因敲除等位基因的近交系小鼠，这进一步证明了修饰基因控制白血病/淋巴瘤的潜伏期和发病率。我们的长期目标是在小鼠中识别这些修饰基因，并确定它们的人类同源基因是否在A-T患者或散发性血液系统恶性肿瘤患者的白血病或淋巴瘤易感性中发挥作用。这一建议的具体目的是在高分辨率(20kb到2Mb之间)定位小鼠A-T模型中的修饰基因，然后根据它们在淋巴肿大中可能扮演的角色对定位区域中的遗传多态进行排序。作图将使用一种新的方法来完成，该方法结合了小鼠异质种群的高作图分辨率和使用转基因等位基因。ATM基因敲除等位基因将通过两个育种世代导入HS/NPT异质种系小鼠。剔除等位基因纯合的小鼠将被监测淋巴瘤的发展和潜伏期，并对大约78,000个SNPs进行基因分型。控制淋巴瘤易感性和潜伏期的基因座将使用分子方差分析方法加以修改，以说明引入基因敲除等位基因所需的育种策略。我们将利用生物信息学的方法来确定标测区域中可能与淋巴肿大有关的基因，并将通过淋巴细胞的基因表达研究和淋巴瘤的杂合性丢失研究来评估这些基因中序列变异的影响。

 DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a heritable syndrome associated with a high risk for leukemia and lymphoma. The syndrome arises in individuals with two defective copies of the ATM gene, but whether a specific A-T patient develops leukemia or lymphoma appears to be controlled not by their ATM mutation(s), but by unknown modifier genes. In the Atm knockout mouse model of A-T, lymphoma incidence and latency depend on the inbred mouse strain carrying the Atm knockout alleles, which is further evidence that modifier genes control leukemia/lymphoma latency and incidence. Our long term objective is to identify these modifier genes in mice and determine if their human homologues play a role in leukemia or lymphoma susceptibility in A-T patients or in patients with sporadic hematological malignancies. The specific aims of this proposal are to map the modifier genes in the mouse A-T model at high resolution (between 20 kb and 2 Mb) and then rank the genetic polymorphisms in the mapped regions according to their likely roles in lymphomagenesis. The mapping will be accomplished using a novel approach which combines the high mapping resolution of murine heterogeneous stocks with the use of a genetically modified allele. The Atm knockout allele will be introgressed into HS/Npt heterogeneous stock mice through two breeding generations. Mice homozygous for the knockout allele will be monitored for lymphoma development and latency, and genotyped for about 78,000 SNPs. Loci controlling lymphoma susceptibility and latency will be identified using an analysis of molecular variance approach modified to account for the breeding strategy needed to introduce the knockout allele. Genes in the mapped regions that are likely to be involved in lymphomagenesis will be identified using bioinformatics approaches and the effects of sequence variations within these genes will be assessed by gene expression studies in lymphoid cells and loss of heterozygosity studies in lymphomas.