Abstract
We have analyzed the pathway for the development of thymic lymphomas and have identified two pathways, the illegitimate V(D)J recombination and the microhomology-mediated end joining, for the deletion formation of Notch1 gene, which is a major oncogene responsible for the development of thymic lymphomas. In the present study, we examined the induction of thymic lymphomas in Rag2Atm-double deficient mice to elucidate the effect of Atm deficiency on thymic lymphoma induction and to analyze the participation of Rag-mediated pathway for the development of thymic lymphomas in Atm-deficient mice. The Rag2Atm-double deficient mice exhibited the reduced frequencies of spontaneous and radiation-induced thymic lymphomas as compared to those in Atm-deficient mice. The Kaplan-Meier tumor-free survival curve revealed that the induction of thymic lymphomas in Rag2Atm-double deficient mice was significantly delayed as compared to that in Atm-deficient mice. The results indicate that thymic lymphomas are induced via both Rag-dependent and Rag-independent pathways in Atm-deficient mice. The frequencies of Notch1 abnormalities in thymic lymphomas were 30%, 56%, and 46% in Rag2, Atm, and Rag2Atm-double deficient mice, respectively, indicating that Notch1 gene is involved in the development of thymic lymphomas in these mice. It is speculated that the rearrangement of Notch1 gene via Rag-dependent and Rag-independent pathways might participate in the development of thymic lymphomas in Atm-deficient mice.
