NO REQUIREMENT FOR V(D)J RECOMBINATION IN P53-DEFICIENT THYMIC LYMPHOMA

The p53 tumor suppressor is activated in response to a variety of cell ular stress signals, although specific in vivo signals that trigger tu mor suppression are unknown. In mouse thymocytes, where p53 inactivati on leads to tumorigenesis, several observations suggest that V(D)J rec ombination of T-cell receptor (TCR) loci could provide a DNA damage si gnal triggering p53-dependent apoptosis and tumor suppression. Inactiv ation of p53 would allow V(D)J driven mutation of additional cancer ge nes, facilitating tumorigenesis, Here, we show that mice with a p53 de ficiency in thymocytes and unable to carry out V(D)J recombination are not impaired in the development of thymoma, Recombination-activating gene (RAG) deficiencies were introduced into both p53(-/-) mice and Tg T Delta N transgenic mice, a strain in which 100% of the mice develop thymoma due to thymocyte-specific inactivation of p53 by a simian viru s 40 T-antigen variant. V(D)J recombination was dispensable for tumori genesis since thymomas developed with or without the RAG-1 or RAG-2 ge ne, although some delay was observed. When V(D)J recombination was sup pressed by expression of rearranged TCR transgenes, 100% of the TgT De lta N mice developed thymoma, surprisingly with reduced latency. Furth er introduction of a RAG deficiency into these mice had no impact on t he timing or frequency of tumorigenesis. Finally, karyotype and chromo some painting analyses showed no evidence for TCR gene translocations in p53-deficient thymomas, although abundant aneuploidy involving freq uent duplication of certain chromosomes was present. Thus, contrary to the current hypothesis, these studies indicate that signals other tha n V(D)J recombination promote p53 tumor suppression in thymocytes and that the mechanism of tumorigenesis is distinct from TCR translocation oncogene activation.