Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA.
Blood. 2011 Oct 27;118(17):4646-56. doi: 10.1182/blood-2011-03-343947. Epub 2011 Aug 9.
Identifying the normal cell from which a tumor originates is crucial to understanding the etiology of that cancer. However, retrospective identification of the cell of origin in cancer is challenging because of the accumulation of genetic and epigenetic changes in tumor cells. The biologic state of the cell of origin likely influences the genetic events that drive transformation. We directly tested this hypothesis by performing a Sleeping Beauty transposon mutagenesis screen in which common insertion sites were identified in tumors that were produced by mutagenesis of cells at varying time points throughout the T lineage. Mutation and gene expression data derived from these tumors were then compared with data obtained from a panel of 84 human T-cell acute lymphoblastic leukemia samples, including copy number alterations and gene expression profiles. This revealed that altering the cell of origin produces tumors that model distinct subtypes of human T-cell acute lymphoblastic leukemia, suggesting that even subtle changes in the cell of origin dramatically affect genetic selection in tumors. These findings have broad implications for the genetic analysis of human cancers as well as the production of mouse models of cancer.
确定肿瘤起源的正常细胞对于了解该癌症的病因至关重要。然而，由于肿瘤细胞中遗传和表观遗传变化的积累，对癌症起源细胞的回顾性鉴定具有挑战性。起源细胞的生物学状态可能会影响驱动转化的遗传事件。我们通过在整个 T 系中在不同时间点对细胞进行诱变，然后直接进行 Sleeping Beauty 转座子诱变筛选来测试这一假设，其中鉴定了常见的插入位点。然后将这些肿瘤的突变和基因表达数据与来自 84 个人 T 细胞急性淋巴细胞白血病样本的面板获得的数据进行比较，包括拷贝数改变和基因表达谱。这表明改变起源细胞会产生模拟人类 T 细胞急性淋巴细胞白血病不同亚型的肿瘤，这表明起源细胞的微小变化会极大地影响肿瘤中的遗传选择。这些发现对人类癌症的遗传分析以及癌症小鼠模型的产生具有广泛的意义。
