Abstract
There might be two types of radiation carcinogenesis. One type is targeted carcinogenesis through radiation-induced DNA damage in target cells. The other is untargeted carcinogenesis through changes in a microenvironment that might indirectly induce genetic changes in unirradiated cells. The existence of untargeted thymic lymphomagenesis was substantiated by the occurrence of untargeted lymphomas induced in unirradiated thymuses transplanted into irradiated mice. The cause of radiation-induced lymphomagenesis and abnormal events occurring during lymphomagenesis are, however, not clear. We examined causative events for lymphoma development during prelymphoma stage in C57BL/6 mice after four consecutive irradiations of 1.8 Gy γ-rays at 1-week intervals. Radiation-induced thymic atrophy was observed until 6 weeks after irradiation. γH2AX foci in thymocytes were formed 6 to 8 weeks after irradiation. Aneuploid cells comprising 41 chromosomes in thymocytes reached 34% in average during 4 to 6 weeks. Chromosomal instability was induced in culture in descendants of irradiated thymocytes, and 8 to 10 weeks after irradiation, 2.3-fold increase in chromatid-type aberrations was observed. When co-cultured with descendants of irradiated thymocytes, bystander effect on chromosomal aberration induction was observed in X-ray-sensitive XRCC4-/- cells. The bystander effect was decreased by treatment with superoxide dismutase and catalase. Notch1 and Bcl11b rearrangements were increased at 10 to 1000-fold frequency in some mice after irradiation. Cell clones exhibiting identical V(D)J recombination in TCRβ locus were observed 2 to 10 weeks after irradiation. Thus, during the early stage of lymphomagenesis, induction of DNA double strand breaks, aneuploidy, delayed chromosomal instability, bystander effect, rearrangements of cancer-related genes, and cell clonality was observed. Induction of these abnormalities might be associated with radiation-induced lymphomagenesis.
