Clonal selection of stable aneuploidies in progenitor cells drives high-prevalence tumorigenesis.
Clonal selection of stable aneuploidies in progenitor cells drives high-prevalence tumorigenesis.
复制标题
DOI：
10.1101/gad.348341.121
复制
发表时间：
2021-08-01
影响因子：
10.5
通讯作者：
Amon A
中科院分区：
文献类型：
--
作者：
Trakala M;Aggarwal M;Sniffen C;Zasadil L;Carroll A;Ma D;Su XA;Wangsa D;Meyer A;Sieben CJ;Zhong J;Hsu PH;Paradis G;Ried T;Holland A;Van Deursen J;Amon A
在这项研究中，Trakala等人研究了染色体的获得和丢失是如何克服非整倍体的有害影响的，这是人类癌症的一个常见特征。他们开发了一种新的小鼠模型，使成年动物的染色体错误分离达到前所未有的水平，他们的结果表明，随机错误分离的初始有害影响被克隆选择所抵消，克隆选择依赖于染色体位置和特定基因的性质，足以驱动癌症。染色体的获得和损失是人类癌症的一个常见特征。然而，这些畸变如何能超过非整倍体的有害影响仍不清楚。现有的染色体不稳定性（CIN）小鼠模型的初步比较表明，非整倍体在这些动物中积累到低水平。因此，我们开发了一种新的小鼠模型，使成年动物的染色体错误分离达到前所未有的水平。在t细胞发育的早期阶段，随机获得和/或失去染色体的细胞被淘汰，但CIN最终导致克隆染色体不平衡的祖细胞扩增。克隆选择导致具有刻板核型的t细胞淋巴瘤的发展，其中含有Myc癌基因的15号染色体具有很高的患病率。从6号染色体表达人类MYC （MYCChr6）足以改变这些淋巴瘤的核型，使其包括普遍的6号染色体。有趣的是，虽然内源性Myc基因座基因切除后，在MYCChr6肿瘤中仍能获得15号染色体，但在删除一个Rad21拷贝后，这条染色体并不能有效地获得，这表明Myc和Rad21在驱动15号染色体获得方面具有协同作用。我们的研究结果表明，随机错分离的初始有害影响被克隆选择所抵消，克隆选择是由染色体位置和某些基因的性质决定的，足以驱动高患病率的癌症。
In this study Trakala et al. investigated how chromosome gains and losses, which are a frequent feature of human cancers, can overcome the detrimental effects of aneuploidy. They developed a novel mouse model that enables unprecedented levels of chromosome missegregation in the adult animal and their results show that the initial detrimental effects of random missegregation are outweighed by clonal selection, which is dependent on chromosomal location and the nature of specific genes and is sufficient to drive cancer. Chromosome gains and losses are a frequent feature of human cancers. However, how these aberrations can outweigh the detrimental effects of aneuploidy remains unclear. An initial comparison of existing chromosomal instability (CIN) mouse models suggests that aneuploidy accumulates to low levels in these animals. We therefore developed a novel mouse model that enables unprecedented levels of chromosome missegregation in the adult animal. At the earliest stages of T-cell development, cells with random chromosome gains and/or losses are selected against, but CIN eventually results in the expansion of progenitors with clonal chromosomal imbalances. Clonal selection leads to the development of T-cell lymphomas with stereotypic karyotypes in which chromosome 15, containing the Myc oncogene, is gained with high prevalence. Expressing human MYC from chromosome 6 (MYCChr6) is sufficient to change the karyotype of these lymphomas to include universal chromosome 6 gains. Interestingly, while chromosome 15 is still gained in MYCChr6 tumors after genetic ablation of the endogenous Myc locus, this chromosome is not efficiently gained after deletion of one copy of Rad21, suggesting a synergistic effect of both MYC and RAD21 in driving chromosome 15 gains. Our results show that the initial detrimental effects of random missegregation are outbalanced by clonal selection, which is dictated by the chromosomal location and nature of certain genes and is sufficient to drive cancer with high prevalence.
登录
查看更多内容
DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Davoli T;Xu AW;Mengwasser KE;Sack LM;Yoon JC;Park PJ;Elledge SJ
通讯作者：
Elledge SJ
PLK1的过表达诱导染色体不稳定性并抑制肿瘤的发育。
影响因子：
16.6
作者：
de Cárcer G;Venkateswaran SV;Salgueiro L;El Bakkali A;Somogyi K;Rowald K;Montañés P;Sanclemente M;Escobar B;de Martino A;McGranahan N;Malumbres M;Sotillo R
通讯作者：
Sotillo R
影响因子：
50.3
作者：
Manchado, Eusebio;Guillamot, Maria;Malumbres, Marcos
通讯作者：
Malumbres, Marcos
影响因子：
5.4
作者：
Cole, Michael D.
通讯作者：
Cole, Michael D.