Changes in the thymic microenvironment lead to radiation-induced thymic lymphomagenesis, but the phenomena are not fully understood. Here we show that radiation-induced chromosomal instability and bystander effects occur in thymocytes and are involved in lymphomagenesis in C57BL/6 mice that have been irradiated four times with 1.8-Gy γ-rays. Reactive oxygen species (ROS) were generated in descendants of irradiated thymocytes during recovery from radiation-induced thymic atrophy. Concomitantly, descendants of irradiated thymocytes manifested DNA lesions as revealed by γ-H2AX foci, chromosomal instability, aneuploidy with trisomy 15 and bystander effects on chromosomal aberration induction in co-cultured ROS-sensitive mutant cells, suggesting that the delayed generation of ROS is a primary cause of these phenomena. Abolishing the bystander effect of post-irradiation thymocytes by superoxide dismutase and catalase supports ROS involvement. Chromosomal instability in thymocytes resulted in the generation of abnormal cell clones bearing trisomy 15 and aberrant karyotypes in the thymus. The emergence of thymic lymphomas from the thymocyte population containing abnormal cell clones indicated that clones with trisomy 15 and altered karyotypes were prelymphoma cells with the potential to develop into thymic lymphomas. The oncogene Notch1 was rearranged after the prelymphoma cells were established. Thus, delayed nontargeted radiation effects drive thymic lymphomagenesis through the induction of characteristic changes in intrathymic immature T cells and the generation of prelymphoma cells.
In a previous communication we showed that ts2 cells, a temperature-sensitive mutant of murine leukemic L5178Y cells, are impaired in karyo-and cyto-kinesis when exposed to high temperatures during the G1 through M phases [14]. Since ts2 cells, when shifted up at the G2 phase, can complete the first cell division normally but are arrested at the second division, the execution point [6] should be located between the G1 and G2 phases [14]. These results suggest that the temperaturesensitivity of ts2 cells is due to a defect in a particular factor which is synthesized or activated during the G1 through G2 phases. To gain insight into the nature of this factor, the precise time of its synthesis or activation had to be determined and the fate of aberrant mitotic cells and multinucleate cells had to be investigated. The process of multinucleation in ts2 cells can be followed with flow cytofluorometry. In the present report we describe the results of these investigations and discuss the mechanism by which a presumed single mutation causes both karyokinetic and cytokinetic abnormalities.
MATERIALS AND METHODSCell culture conditions. Mutant ts2 cells were isolated from murine leukemic cells L5178Yand were grown in enriched Eagle's MEM medium supplemented with 10 %
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