Ohi H, Mishima Y, Kamimura K, Maruyama M, Sasai K, Kominami R
Department of Molecular Genetics, Graduate School of Medical and Dental Sciences, Niigata University, Asahimachi, Niigata, Japan.
Oncogene. 2007 Aug 9;26(36):5280-9. doi: 10.1038/sj.onc.1210325. Epub 2007 Feb 26.
Whole-body gamma-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 TCRbeta 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 TCRbeta 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.
对小鼠进行全身γ射线照射会导致胸腺萎缩，在萎缩的胸腺中可以发现一群带有突变的癌前细胞。因此，不仅在胸腺淋巴瘤中，而且在照射后不同时间的萎缩胸腺中，都检测了Bcl11b、Ikaros、Pten、Notch1和Myc的克隆生长及DNA变化。早在照射后30天，在一部分萎缩胸腺中，通过TCRβ受体基因座重排的独特模式检测到了克隆扩增。这种扩增可能部分归因于重排的TCRβ信号传导，因为将带有重排基因座和野生型基因座的骨髓细胞移植到严重联合免疫缺陷小鼠中，显示出重排胸腺细胞在萎缩胸腺中的优先生长。在淋巴瘤和萎缩胸腺中都高频发现了Bcl11b的杂合性缺失（LOH）和Myc的三体性，相反，Ikaros和Pten的LOH在萎缩胸腺中很少见，但在淋巴瘤中很普遍。Notch1激活仅在晚期在淋巴瘤和萎缩胸腺中被检测到。在Bcl11b(+/-)小鼠诱导的萎缩胸腺中也发现了类似的DNA变化模式。这些结果表明淋巴瘤发生过程中基因变化的顺序，Bcl11b和Myc处于早期；而Ikaros、Pten和Notch1处于晚期。
