Abstract
Heterozygous germline mutations in DNA mismatch repair (MMR) genes are the cause of hereditary nonpolyposis colorectal cancer (HNPCC). In addition, homozygous germline mutations of MMR genes are also manifested by an early onset of childhood leukemias. We showed Mlh1-deficient mice spontaneously developed thymic lymphomas from 3 month after birth at the frequency of 61%. After X-ray-irradiation at 2-week- and 10-week-old mice, the frequency increased to 87% and 93%, respectively. Irradiation induced tumor more rapidly. The aim of this study was to elucidate the effect of radiation exposure on Ikaros mutation.
The thymic lymphomas developed in unirradiated, irradiated at 2-week- and 10-week-old Mlh1-deficient mice were analyzed by Western blot and sequencing.
The frequent lack of Ikaros protein was found in unirradiated, 2-week-old irradiated group at the frequency of 71%(5/7) and 85%(11/13), respectively, but that in 10-week-old irradiated group reduced to 46%(6/13). All lymphomas lacking Ikaros protein harbored the frameshift mutations in mononucleotide repeat sequence within Ikaros gene. On the other hand, lymphomas expressing Ikaros protein of 10-week-old irradiated group harbored the frequent point mutations (71%; 5/7) in DNA-binding domain. These results show the spectrum of Ikaros mutation is altered in an age-at-exposure dependent fashion in Mlh1-deficient mice.
