To distinguish the contributions of these factors to lymphoma susceptibility, we examined mouse mutants in which DNA repair and genome stability were separated from defective lymphocyte development and immune surveillance. However, it is unclear whether the elevated cancer risk in these patients results from DNA repair defects or defective immunosurveillance in the absence of mature lymphocytes. Thus, genetic defects in DSB repair components arrest lymphocyte development, causing severe immunodeficiency (reviewed in Ref. Faithful execution of the site-specific recombination process that assembles functional T- and B-cell antigen receptor genes from dispersed variable (V), diversity (D), and joining (J) coding segments is required for T- and B-cell maturation and depends upon ubiquitous DSB repair pathways (6). Lymphomas of both T- and B-cell origin are also common among patients with primary immunodeficiencies arising from genetic defects in DNA repair (reviewed in Ref. 4) are associated with an increased incidence of malignancies, particularly lymphoma and leukemia. Acquired immunodeficiencies caused by cancer chemotherapy (2), posttransplant immunosuppressive therapy (3), and HIV infection (reviewed in Ref. The immune system is thought to play a vital role in the surveillance of and protection against the growth of tumor cells (reviewed in Ref. The high incidence of autoimmune diabetes and lymphoma in immunodeficiency NOD mice suggests the presence of genetic modifiers that affect lymphocyte homeostasis. Strikingly, the lymphoma incidence in both strains was greater in females, mirroring the greater incidence of autoimmune type 1 diabetes in NOD females than in males. RAG-2 −/−) display a high incidence of lymphoma of both T- and B-cell origin compared with these mutations on other genetic backgrounds. We report that NOD mice deficient in mature B cells (NOD.μ MT) or mature T and B cells (NOD. To distinguish between the contributions of immunodeficiency and defective double-strand DNA break repair to lymphoma susceptibility on the NOD background, we examined the incidence, phenotype, and molecular mechanisms of lymphoma development in two immunodeficient NOD strains with normal DNA repair function. This mutation arrests lymphocyte development secondary to a generalized defect in double-strand DNA break repair that compromises V(D)J recombination. scid) have an incidence of pro-T-cell lymphoma far in excess of scid mutants on other genetic backgrounds. NOD mice congenic for the severe combined immunodeficiency scid mutation (NOD. In the nonobese diabetic (NOD) mouse, a murine model of autoimmune type 1 diabetes and Sjögren’s syndrome, T cells are apoptosis resistant compared with other mouse strains, a feature thought to potentiate their autoimmune function. These mechanisms also influence the development of autoimmune disease, where dysregulated lymphocyte homeostasis has been implicated in expansion of autoreactive T cells. Transformed lymphocytes exhibit aberrant growth potential resulting from enhanced proliferation and resistance to apoptotic stimuli.

Nod scid mouse