Nature of nontargeted radiation effects observed during fractionated irradiation-induced thymic lymphomagenesis in mice

Abstract

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.

Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy

“…Clonal expansion of cells with LOH at the Bcl11b locus has been reported as being one of the earliest detectable changes (along with Myc amplification) in the thymus post-irradiation but prior to the onset of lymphoma [ 37 ]. The presence of Notch1 Type 1 deletion-bearing cells in the normal mouse thymus [ 38 ] suggests that activating Notch1 deletions in the TL could result from selective expansion of cells with pre-existing spontaneous deletions, yet other evidence indicates that the recombination-mediated deletions are a later spontaneous event in the carcinogenic sequence [ 37 , 39 ], with no increase in deletion frequency in TL from irradiated compared to unirradiated mice [ 31 ]. Since studies of large panels of T-ALL have failed to find equivalent recombination-mediated deletions in the human NOTCH1 gene [ 32 ], this represents a mouse-specific tumour susceptibility that may contribute to their increased vulnerability to radiation-induced T cell tumours; though, the finding of a NOTCH1 Type 2 activating deletion (not recombination mediated) in a T-ALL patient [ 40 ] demonstrates that the mechanism has prima facie relevance to human cancers.…”

Mechanisms Underlying the Development of Murine T-Cell Lymphoblastic Lymphoma/Leukemia Induced by Total-Body Irradiation

“…They also noted that chromosomally aberrant cells were present in 25 of 26 (96%) of the thymic lymphomas examined, and the most frequent abnormality observed was trisomy or partial trisomy of chromosome 15 (16/26, 62%), which was consistent with earlier studies [ 45 , 46 , 47 , 48 , 49 ]. In addition, genomic alterations of the Ikaros / IKZF1 tumor suppressor gene and Notch1 oncogene were frequently observed in murine radiation-induced thymic lymphomas [ 50 , 51 , 52 , 53 , 54 ]. With the use of the distinct patterns of rearrangements at the T-cell receptor β (TCR-β) loci, Ohi et al found that clonal expansions were detected in a fraction of atrophic thymuses 30 days after irradiation [ 55 ].…”

“…In 2013, Tsuji et al published the results that examine the dynamic changes in the cell population that occurred within the thymuses of B6 female mice at various time points after FX treatment [ 52 ]. Their analysis included the course of the dynamic cytogenetic as well as genomic changes in the thymocyte populations, and clonal analysis of pre-lymphoma and established lymphoma cells using TCRβ gene rearrangements.…”