The evolution of thymic lymphomas in p53 knockout mice.
The evolution of thymic lymphomas in p53 knockout mice.
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DOI：
10.1101/gad.252148.114
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发表时间：
2014-12-01
影响因子：
10.5
通讯作者：
Levine AJ
中科院分区：
文献类型：
--
作者：
Dudgeon C;Chan C;Kang W;Sun Y;Emerson R;Robins H;Levine AJ
Germline deletion of p53 in mice gives rise to spontaneous thymic lymphomas. Dudgeon et al. demonstrate that p53 knockout thymic lymphomas arise in an oligoclonal fashion, with tumors evolving dominant clones over time. All of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement. This was followed by the amplification or overexpression of cyclin Ds and Cdk6. This study details the mutational evolution of thymic lymphoma tumorigenesis. Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRβ sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors’ driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas.
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