Comparison of Ikaros, p53 and Kras point mutation in mouse thymic lymphomas induced by simultaneous exposure to X-ray and N-ethyl-N-nitrosourea.

Background: It is well known that several oncogenes or tumor suppressor genes are mutated in carcinogen-induced tumors. However, available data are quite small about the accumulation of mutation after combined exposure to radiation and chemical carcinogens. In the present study, we aimed to determine the change in frequency and spectrum of Ikaros, p53 and Kras point mutations in thymic lymphomas of B6C3F1 mice, which were simultaneously exposed to X-rays and ENU.\nMaterials and Methods: Beginning at 4 weeks of age, a group of female B6C3F1 mice was weekly exposed to whole-body X irradiation at 0.2 0.4 0.8 and 1.0 Gy for 4 consecutive weeks and given N-ethyl-N-nitrosourea (ENU) in drinking water at 50, 100 and 200 ppm for 4 consecutive weeks at the same time. Collected lymphomas were examined for the mutations of Ikaros, p53 and Kras.\nResults and Discussion:The simultaneous exposure to X-rays and ENU increased thymic lymphoma incidence in a synergistic manner at high doses. Ikaros and p53 mutation frequency significantly increased in a supra-additive manner, but, Kras mutation frequency showed not supra-additive in the simultaneous exposure. Increase in Ikaros mutation was ascribed in part to G to T/C base substitution, which were newly generated by combined exposure. In addition, T to C and G to A substitution were supra-additive compared to single exposure. Point mutation of G to C and T to C/G were newly generated in p53. The mutations of Ikaros and p53 distributed mainly in the DNA binding domain. And the distribution of mutation was very wide in simultaneous exposure compared to single exposure. Whereas, most mutated position of Kras was G to A at codon 12. Newly generated and supra-additive mutation were not detected in Kras. The results suggest Ikaros and p53 mutation contributed more to lymphomagenesis by simultaneous exposure than Kras, and simultaneous exposure provides new generated and complex carcinogenic mechanism.KIDS workshop 2009 in NIR

Splenic lymphomas of Mlh1-deficient mice induced by in utero irradiation are derived from invariant natural killer T cell.

Deficiencies in DNA mismatch repair (MMR) result in replication errors that cause frameshift mutations and/or point mutations within key tumor suppressor genes or oncogenes. Homozygous germline mutations of MMR genes, such as MLH1, MSH2 and PMS2, are manifested by early onset childhood T- or B-cell leukemia. Mlh1-/- mice develop aggressive thymic lymphomas. We previously showed that spontaneously developed Mlh1-/- thymic lymphomas harbored frequent frameshift mutations in Ikaros, a master transcription factor of lymphoid lineage commitment and differentiation. In this study, we examined the effect of fetal radiation exposure on lymphomgenesis in Mlh1-/- mice. Exposure to radiation after birth increased the incidence of thymic lymphomas and shortened their latency. Point mutations and frameshift mutation in Ikaros were generated in radiation-induced lymphomas. In utero radiation exposure, unexpectedly, resulted in no effect on thymic lymphomagenesis, but accelerated splenic lymphomagenesis. Analysis of TCRa and b rearrangement revealed that a half of splenic lymphomas and all lymphomas expressing TCR expressed the Va14−Ja18 rearrangement paired with either Vb-8, -7 or -2, which is specific for invariant natural killer T cell. Mechanisms of lymphomagenesis of iNKT cells are remained to be studied.6th International Workshop of Kyoto T Cell Conference (KTCC2013