Abstract
Deficiencies in DNA mismatch repair (MMR) result in replication errors within key tumor suppressor genes or oncogenes, and cause hereditary nonpolyposis colorectal cancer (HNPCC). Hematological malignancy with microsatellite instability is also associated with defective MMR, but little is known about the target genes for MMR. Here we identified Ikaros, a master transcription factor of lymphoid lineage commitment and differentiation, as a mutational target in spontaneous and radiation-induced T-cell lymphomas in Mlh1-deficient mice. Three quarters of lymphomas lacked Ikaros protein expression, which resulted from a frameshift mutation that created a stop codon. Mononucleotide repeat sequences at 1029–1034(C)6 and 1567–1572(G)6 in Ikaros were mutational hot spots with a one-base deletion occurring with a frequency of 45 and 50%, respectively. Point mutations and splicing alterations were also observed. In total, 85% of the lymphomas showed aberrations in Ikaros. The characteristic of Mlh1-deficient lymphomas is harboring of multiple mutations simultaneously in the same tumor, displaying a combination of two frameshift mutations at different repeats, frameshift and point mutations, and/or deletion mutations. This is the first report of Ikaros mutations coupled with Mlh1 deficiency in lymphomagenesis.
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Acknowledgements
We gratefully acknowledge Dr Michael Liskay (Department of Molecular and Medical Genetics, Oregon Health Sciences University, Oregon, USA) for providing the Mlh1-knockout mice and for the helpful comments on the manuscript. We thank Mizuho Igo and Eriko Obara for technical assistance, and the Division of Animal Facility staff for helps with laboratory analysis and animal maintenance. This study was supported partly by a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, a grant of ‘Ground-based Research Announcement for Space Utilization’ promoted by the Japan Space Forum and a grant from the Long-range Research Initiative of the Japan Chemical Industry Association.
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Kakinuma, S., Kodama, Y., Amasaki, Y. et al. Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice. Oncogene 26, 2945–2949 (2007). https://doi.org/10.1038/sj.onc.1210100
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DOI: https://doi.org/10.1038/sj.onc.1210100
