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

摘要

The majority of Atm-deficient mice die of malignant thymic lym- phoma by 4--5 mo of age. Cytogenetic abnormalities in these tumors are consistently identified within the Tcr α/δ locus, sug- gesting that tumorigenesis is secondary to aberrant responses to double-stranded DNA breaks that occur during V(D)J recombina- tion. Since V(D)J recombination is a recombinase-activating gene (RAG)-dependent process, we generated Rag2~-/-Atm~-/- mice to assess the requirement for RAG-dependent recombination in thy- mic lymphomagenesis. In contrast to expectation, the data pre- sented here indicate that development of malignant thymic lym- phoma in Atm~-/- mice is not prevented by loss of RAG-2 and thus is not dependent on V(D)J recombination. Malignant thymic lym- phomas in Rag2~-/-Atm--l-- mice occurred at a lower frequency and with a longer latency as compared with Atm~-/- mice. Importantly. cytogenetic analysis of these tumors indicated that multiple chro- mosomal abnormalities occurred in each tumor, but that none of these involved the Tcr α/δ locus. Nonmalignant peripheral T cells from TCR-transgenic Rag2~-/-Atm~-/- mice also revealed a substan- tial increase in translocation frequency. suggesting that these translocations are early events in the process of tumorigenesis. These data are consistent with the hypothesis that the major mechanism of tumorigenesis in Atm~-/- mice is via chromosomal translocations and other abnormalities that are secondary to ab- errant responses to double-stranded DNA breaks. Furthermore, these data suggest that V(D)J recombination is a critical. but not essential. event during which Atm-deficient thymocytes are sus- ceptible to developing chromosome aberrations that predispose to malignant transformation.