Corral J, Lavenir I, Impey H, Warren A J, Forster A, Larson T A, Bell S, McKenzie A N, King G, Rabbitts T H
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
Cell. 1996 Jun 14;85(6):853-61. doi: 10.1016/s0092-8674(00)81269-6.
Homologous recombination in embryonal stem cells has been used to produce a fusion oncogene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncogenes in human malignancies. AF9 sequences were fused into the mouse Mll gene so that expression of the Mll-AF9 fusion gene occurred from endogenous Mll transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the Mll promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a general strategy to create fusion oncogenes for studying their role in tumorigenesis.
胚胎干细胞中的同源重组已被用于产生融合致癌基因，从而模拟染色体易位，而这种易位在人类恶性肿瘤中经常导致肿瘤特异性融合致癌基因的形成。AF9序列被融合到小鼠Mll基因中，使得Mll-AF9融合基因的表达由内源性Mll转录控制元件驱动，就如同在人类白血病中发现的t(9;11)一样。携带融合基因的嵌合小鼠发生了肿瘤，尽管Mll启动子具有广泛的活性，但这些肿瘤仅限于急性髓系白血病。在可察觉疾病出现之前，外周血中的胚胎干细胞衍生物会出现扩增。同源重组的这种新用途正式证明了染色体易位会导致恶性肿瘤，并提供了一种创建融合致癌基因以研究其在肿瘤发生中作用的通用策略。
