Chromosomal instability and supernumerary centrosomes represent precursor defects in a mouse model of T-cell lymphoma.
Chromosomal instability and supernumerary centrosomes represent precursor defects in a mouse model of T-cell lymphoma.
复制标题
染色体不稳定性和多余中心体代表 T 细胞淋巴瘤小鼠模型中的前体缺陷。
DOI：
10.1158/0008-5472.can-07-1666
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发表时间：
2007
期刊：
影响因子：
11.2
通讯作者：
Knudson,CMichael
中科院分区：
文献类型：
--
作者：
vandeWetering,ChristopherI;Horne,MaryC;Knudson,CMichael
癌发生的一个标志是对细胞死亡的抵抗。然而，最近的研究表明，Bax的表达增加细胞凋亡和促进肿瘤的发生。在这项研究中，我们假设Bax通过增加染色体不稳定性（CIN）促进肿瘤形成。与这一假设一致，光谱核型分析（SKY）的淋巴瘤来源于LCK-38/1小鼠一致的非整倍体。为了确定CIN是否先于肿瘤形成，对来自年轻癌前小鼠的胸腺细胞进行定量细胞遗传学分析、SKY分析和定量中心体染色。在6至10周龄之间，来自表达p53+/+或p53-/-的小鼠的胸腺具有增加的非整倍体细胞百分比以及具有额外中心体的细胞的增加。对于3- 6周龄的小鼠，Bax表达增加了p53−/−小鼠的非整倍体和额外中心体，但在p53+/+动物中没有。重要的是，非整倍体和额外的中心体都被Bcl-2减弱。值得注意的是，SKY分析显示，在3至6周龄的p53−/− β表达小鼠中存在多个独立的非整倍体群体。这些结果表明，寡克隆非整倍体和多余的中心体是Bcl-2家族和CIN之间的新的联系，并支持Bcl-2诱导的淋巴瘤形成的早期标志。这些数据为Bcl-2家族对致癌作用的矛盾作用提供了一个有吸引力的模型，这些作用已在人类和小鼠的多项研究中观察到。[Cancer Res 2007;67（17）：8081-8]
A hallmark of carcinogenesis is resistance to cell death. However, recent studies indicate that Bax expression increased apoptosis and promoted oncogenesis. In this study, we hypothesized that Bax promotes tumor formation by increasing chromosomal instability (CIN). Consistent with this hypothesis, spectral karyotype analysis (SKY) of lymphomas derived from Lck-Bax38/1 mice were consistently aneuploid. To determine if CIN precedes tumor formation, quantitative cytogenetic analysis, SKY analysis, and quantitative centrosome staining were done on thymocytes from young premalignant mice. Between 6 and 10 weeks of age, thymi from Bax-expressing mice (either p53+/+ or p53−/−) had an increased percentage of aneuploid cells as well as an increase in cells with supernumerary centrosomes. For 3- to 6-week-old mice, Bax expression increased aneuploidy and supernumerary centrosomes in p53−/− mice but not in p53+/+ animals. Importantly, both aneuploidy and supernumerary centrosomes were attenuated by Bcl-2. Remarkably, SKY analysis showed multiple independent aneuploid populations in the p53−/− Bax-expressing mice between 3 and 6 weeks of age. These results indicate that oligoclonal aneuploidy and supernumerary centrosomes are early hallmarks of Bax-induced lymphoma formation and support a novel link between the Bcl-2 family and CIN. The data provide an attractive model for the paradoxical effects of the Bcl-2 family on carcinogenesis that have been observed in multiple studies of both humans and mice. [Cancer Res 2007;67(17):8081–8]