23. Development of Thymic Lymphomas by Ionizing Radiation in Scid Mice
Toshiaki Ogiu, Hiroko Ishii-Ohba, Shigeru Kobayashi, Mayumi Nishimura, Yoshiya Shimada, Hideo Tsuji, Hideki Ukai, Fumiaki Watanabe, Fumio Suzuki, and Toshihiko Sado
Keywords: Scid mice, radiation-induced thymic lymphomas, oncogenes, Ras, Notch1
The Scid mouse shows a severe combined immunodeficiency because it lacks both T- and B-cell functions caused by highly repressed V(D)J recombination in immunocyte-development due to drastic reduction of ability to rejoin coding segments by DNA-dependent protein kinase (DNA-PK). For the analysis of effects of Scid mutation on radiation- carcinogenesis, Scid (Scid homozygous), C.B-17 (wild-type) and their (C.B-17xScid)F1 hybrid (Scid heterozygous) were used.
Regarding acute effects of ionizing radiation, Scid mice were more sensitive than F1 and wild-type mice, not only in vivo, but also in vitro. In long-term carcinogenesis experiments, groups of Scid, C.B-17 and F1 mice were exposed to a single whole-body radiation with 1 - 3 Gy gamma rays. Most irradiated Scid mice died with thymic lymphomas 20 to 40 weeks after irradiation. By contrast, C.B-17 and F1 mice survived longer, and incidences of thymic lymphomas were low.
Oncogenes involved in thymic lymphoma development were analyzed. The possible role of Ras activation in spontaneous and radiation-induced lymphomas of the Scid mice was examined. However, neither activated K-Ras nor N-Ras genes were detected in spontaneous lymphomas and no N-Ras mutations were detected in radiation-induced lymphomas. Although K-Ras mutations increased as a function of dose in radiation-induced lymphomas, they were rather infrequent.
Rearrangements of Notch1 gene were analyzed using Scid and wild-type thymic lymphoma cell lines established in this laboratory. About one third of radiation-induced Scid thymic lymphomas exhibited DNA rearrangements whereas one fifth of wild-type lymphomas displayed abnormalities. Analysis of abnormalities revealed that intragenic deletions and insertions of IAP or MuLV were observed in thymic lymphomas derived from Scid and wild-type mice. These data suggest that the defective Scid gene participates in the formation of DNA rearrangements in Notch1 gene and that dysregulated Notch1 plays a role in murine thymic lymphomagenesis.
It may be concluded that there is a close relationship between radiosensitivity and development of thymic lymphomas in Scid homozygotes. Development of thymic lymphomas in Scid mice may correlate with reduced DNA-PK activity that is high in the thymus as compared with other organs, and might correlate with an increase in the yield of deletion or insertion in oncogene(s) rather than point mutation
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