The majority of non-Hodgkin's lymphomas (NHL) are of B cell origin and harbor oncogenic chromosome translocations involving the IgH locus. Phenotypic and molecular studies suggest that these tumors arise from components of germinal centers, which develop during coordinated T and B cell immune responses. Clinical and epidemiologic observations have noted an increased incidence of NHL in certain types of chronic or aberrant immune responses. Thus, critical genetic lesions leading to malignant transformation are linked to antigen stimulation of B cells. Germinal center reactions involve physiologic genomic instability at Ig loci t h rough somatic hypermutation, V(D)J recombination, and isotype class switching. DNA breaks created during these processes may contribute to oncogenic translocations. Previous work in this laboratory has shown that mice with combined scid and p53-/- mutations develop pro-B cell tumors bearing recurrent IgH locus translocations. These tumors are dependent on V(D)J recombinase activity, indicating that they arise from impaired rejoining of IgH locus DNA breaks in the setting of defective cellular responses to DNA damage. In scid p53-/- mice transgenic expression of an IgH+L transgene specific for hen egg lysozyme (aHELtg) rescued development of mature B cells. The transgene also suppressed the occurrence of translocation-associated B lineage tumors, consistent with inhibition of V to DJ rearrangement through the process of allelic exclusion. In aHELtg mice on the wild-type background, i m m u nization with the cognate HEL antigen induced endogenous V(D)J recombination and expression of Igl in a subset of B cells, and induced DNA breaks in the Igk and IgH loci. aHELtg mice on the translocation-susceptible scid p53-/- background present an opportunity to investigate how the induction of DNA breaks in Ig loci during immune responses may contribute to oncogenic chromosome translocations. These studies may improve the understanding of how perturbations in immunity may contribute to NHL.
