Weiss W A, Aldape K, Mohapatra G, Feuerstein B G, Bishop J M
G.W. Hooper Foundation, and Department of Neurology, University of California, San Francisco 94143-0552, USA.
EMBO J. 1997 Jun 2;16(11):2985-95. doi: 10.1093/emboj/16.11.2985.
The proto-oncogene MYCN is often amplified in human neuroblastomas. The assumption that the amplification contributes to tumorigenesis has never been tested directly. We have created transgenic mice that overexpress MYCN in neuroectodermal cells and develop neuroblastoma. Analysis of tumors by comparative genomic hybridization revealed gains and losses of at least seven chromosomal regions, all of which are syntenic with comparable abnormalities detected in human neuroblastomas. In addition, we have shown that increases in MYCN dosage or deficiencies in either of the tumor suppressor genes NF1 or RB1 can augment tumorigenesis by the transgene. Our results provide direct evidence that MYCN can contribute to the genesis of neuroblastoma, suggest that the genetic events involved in the genesis of neuroblastoma can be tumorigenic in more than one chronological sequence, and offer a model for further study of the pathogenesis and therapy of neuroblastoma.
原癌基因MYCN在人类神经母细胞瘤中常发生扩增。扩增导致肿瘤发生这一假设从未得到直接验证。我们构建了在神经外胚层细胞中过表达MYCN并发生神经母细胞瘤的转基因小鼠。通过比较基因组杂交分析肿瘤发现，至少七个染色体区域存在增减变化，所有这些区域与在人类神经母细胞瘤中检测到的类似异常具有同源性。此外，我们还表明，MYCN剂量增加或肿瘤抑制基因NF1或RB1中的任何一个存在缺陷，均可增强转基因导致的肿瘤发生。我们的结果提供了直接证据，证明MYCN可促成神经母细胞瘤的发生，表明神经母细胞瘤发生过程中涉及的遗传事件可能按不止一种时间顺序具有致瘤性，并为进一步研究神经母细胞瘤的发病机制和治疗提供了一个模型。
