Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation
Multi-step lymphomagenesis deduced from DNA changes in thymic lymphomas and atrophic thymuses at various times after γ-irradiation
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DOI：
10.1038/sj.onc.1210325
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发表时间：
2007-08-09
期刊：
影响因子：
8
通讯作者：
Kominami, R.
中科院分区：
文献类型：
--
作者：
Ohi, H.;Mishima, Y.;Kominami, R.
对小鼠进行全身γ射线照射会导致胸腺萎缩，在胸腺中可以发现具有突变的癌前细胞群。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，检查了Bcl 11b、Ikaros、Pten、Notch 1和Myc的克隆生长和DNA变化。克隆扩增检测到的不同模式的重排在TCR β受体基因座的一部分萎缩的胸腺在辐射后30天。这种扩增可能部分归因于重排的TCR β信号传导，因为将具有重排和野生型基因座的骨髓细胞转移到严重联合免疫缺陷小鼠中显示重排的胸腺细胞在萎缩的胸腺中优先生长。Bcl 11 b杂合性缺失（洛）和Myc三体在萎缩性胸腺和淋巴瘤中均出现频率较高，而Ikaros和Pten的洛在萎缩性胸腺中少见，而在淋巴瘤中普遍存在。Notch 1激活检测淋巴瘤和萎缩的胸腺只有在晚期。在Bcl 11b（+/-）小鼠中诱导的萎缩胸腺中发现了类似的DNA变化模式。提示淋巴瘤发生过程中的基因变化顺序为：Bcl 11b和Myc处于早期，Ikaros、Pten和Notch 1处于晚期。
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 TCR beta 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 TCR beta 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.