Genomic characterisation of Eμ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene.
Genomic characterisation of Eμ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene.
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DOI：
10.1038/ncomms14581
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发表时间：
2017-03-06
影响因子：
16.6
通讯作者：
Johnstone RW
中科院分区：
文献类型：
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作者：
Lefebure M;Tothill RW;Kruse E;Hawkins ED;Shortt J;Matthews GM;Gregory GP;Martin BP;Kelly MJ;Todorovski I;Doyle MA;Lupat R;Li J;Schroeder J;Wall M;Craig S;Poortinga G;Cameron D;Bywater M;Kats L;Gearhart MD;Bardwell VJ;Dickins RA;Hannan RD;Papenfuss AT;Johnstone RW
Eμ-Myc小鼠是一种广泛使用的MYC驱动的恶性肿瘤模型；然而，到目前为止，只有部分表征MYC合作突变导致自发性淋巴瘤发生。在这里，我们对自发产生的Eμ-Myc淋巴瘤进行测序，以确定转基因结构、体细胞突变和结构改变。我们在prc1样成分和bcl6协同抑制基因Bcor中发现了频繁的破坏性突变。此外，我们发现意外的多基因病变涉及Cdkn2a缺失和其他癌症基因，包括Nras、Kras和Bcor。这些发现挑战了假设的Eμ-Myc淋巴瘤双击模型，并证明了Bcor在体内抑制肿瘤发生中的功能作用。Eμ-Myc淋巴瘤小鼠模型在该疾病的研究中具有不可估量的价值。在这里，作者使用多种测序策略来分析这些小鼠的肿瘤，并发现Bcor中复发的失活突变，这表明该基因在Myc信号传导中具有负作用。
The Eμ-Myc mouse is an extensively used model of MYC driven malignancy; however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising Eμ-Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor. Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nras, Kras and Bcor. These findings challenge the assumed two-hit model of Eμ-Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis. The Eμ-Myc lymphoma mouse model has been invaluable in the study of this disease. Here, the authors use multiple sequencing strategies to analyse the tumours in these mice and find recurrent inactivating mutations in Bcor, suggesting that this gene has a negative role in Myc signalling.