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Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation

Oncogene volume 26, pages 5280–5289 (2007)Cite this article

Abstract

Whole-body γ-irradiation to mice causes thymic atrophy where a population of precancerous cells with mutation can be found. Thus, clonal growth and DNA changes at Bcl11b, Ikaros, Pten, Notch1 and Myc were examined in not only thymic lymphomas but also in atrophic thymuses at various times after irradiation. Clonal expansion was detected from the distinct patterns of rearrangements at the TCRβ receptor locus in a fraction of atrophic thymuses at as early as 30 days after irradiation. This expansion may be in part owing to the rearranged TCRβ signaling because the transfer of bone marrow cells with the rearrangement and the wild-type locus into severe-combined immunodeficiency mice showed preferential growth of the rearranged thymocytes in atrophic thymus. Loss of heterozygosity (LOH) at Bcl11b and trisomy of Myc were found at high frequencies in both lymphomas and atrophic thymuses, and in contrast, LOH at Ikaros and Pten were rare in atrophic thymuses but prevalent in lymphomas. Notch1 activation was detected in lymphomas and in atrophic thymuses only at a late stage. Similar patterns of DNA changes were found in atrophic thymuses induced in Bcl11b+/− mice. These results suggest the order of genetic changes during lymphomagenesis, Bcl11b and Myc being at the early stage; whereas Ikaros, Pten and Notch1 at the late stage.

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Acknowledgements

We thank O Niwa and A Naito for helpful comments on the paper and PCR analysis, respectively. This work was supported by Grants-in-Aid for Cancer Research from the Ministries of Education, Science, Art and Sports, and was also supported by Grants-in-Aid for Cancer Research (13-2) from the Ministry of Health, Labor and Welfare of Japan.

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Authors and Affiliations

  1. Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi, Niigata, Japan

    H Ohi, Y Mishima, K Kamimura, M Maruyama, K Sasai & R Kominami

  2. Center for Transdisciplinary Research, Niigata University, Asahimachi, Niigata, Japan

    Y Mishima & R Kominami

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  1. H Ohi
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  2. Y Mishima
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  3. K Kamimura
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Correspondence to R Kominami.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Ohi, H., Mishima, Y., Kamimura, K. et al. Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation. Oncogene 26, 5280–5289 (2007). https://doi.org/10.1038/sj.onc.1210325

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