Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice

The majority of Atm-deficient mice die of malignant thymic lymphoma by 4-5 mo of age. Cytogenetic abnormalities in these tumors are consistently ident ified within the Tcr alpha/delta locus, suggesting that tumorigenesis is se condary to aberrant responses to double-stranded DNA breaks that occur duri ng V(D)J recombination. Since V(D)J recombination is a recombinase-activati ng gene (RAG)-dependent process, we generated Rag2(-/-)Atm(-/-) mice to ass ess the requirement for RAG-dependent recombination in thymic lymphomagenes is, In contrast to expectation, the data presented here indicate that devel opment of malignant thymic lymphoma in Atm(-/-) mice is not prevented by lo ss of RAG-2 and thus is not dependent on V(D)I recombination. Malignant thy mic lymphomas in Rag2(-/-)Atm(-/-) mice occurred at a lower frequency and w ith a longer latency as compared with Atm(-/-) mice. Importantly, cytogenet ic analysis of these tumors indicated that multiple chromosomal abnormaliti es occurred in each tumor, but that none of these involved the Tcr alpha/de lta locus. Nonmalignant peripheral T cells from TCR-transgenic Rag2(-/-)Atm (-/-) mice also revealed a substantial increase in translocation frequency, suggesting that these translocations are early events in the process of tu morigenesis. These data are consistent with the hypothesis that the major m echanism of tumorigenesis in Atm(-/-) mice is via chromosomal translocation s and other abnormalities that are secondary to aberrant responses to doubl e-stranded DNA breaks. Furthermore, these data suggest that V(D)J recombina tion is a critical, but not essential, event during which Atm-deficient thy mocytes are susceptible to developing chromosome aberrations that predispos e to malignant transformation.