Abstract
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. Heterozygous germline mutations in MMR genes are the cause of hereditary nonpolyposis colorectal cancer (HNPCC). In these cancers, mutations in mononucleotide repeat sequences in TGFbRII or BAX have been frequently reported. Homozygous germline mutations of MMR genes are also manifested by an early onset of childhood T- or B-cell leukemias, but the target gene was not identified yet. We previously showed the lymphomas of Mlh1-deficient mice have normal type of TgfbrII, although insertional mutation in this gene has been reported in Msh2-deficient mouse lymphomas. In this study, we focused on Ikaros as a target gene of Mlh1-deficiency and elucidated the frequency and spectrum of the mutation.
Most of the spontaneously induced lymphomas lacked Ikaros protein at the frequency of 71%. This was resulted from frameshift mutations, most of which were one-base deletion in a mononucleotide repeat sequence that created a stop codon. These mutations were found in 86% of Mlh1-deficient lymphomas, but rarely found in radiation- and chemical-induced mouse lymphomas or in human leukemias. Thus, Ikaros is a most likely target for MMR deficiency-mediated mutation during the development of lymphomagenesis.
