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.
Ataxia-telangiectasia (A-T) is a heritable syndrome resulting from germline mutations in the ATM gene. About 38% of A-T patients develop malignancies, predominantly leukemia and lymphoma. Clinical observations and an experimental study in Atm knockout mice implicate modifier genes in the incomplete penetrance of the leukemia/lymphoma phenotype. The goal of the proposed research is to identify these modifier genes in a murine model of A-T as a prelude to identifying their human homologues. Relevance to public health: Identifying ATM leukemia/lymphoma modifier genes could improve the management of A-T patients by leading to a genetic test that would provide more accurate prognoses for individual patients. The identification of the modifier genes and the pathways in which they operate might point to rational measures to reduce the risks of hematological malignancies in these patients. In addition to its relevance for A-T patients, identification of the modifier genes may also be germane to sporadic leukemias and lymphomas.
