Generation of conditional ALK F1174L mutant mouse models for the study of neuroblastoma pathogenesis.
Generation of conditional ALK F1174L mutant mouse models for the study of neuroblastoma pathogenesis.
复制标题
生成用于研究神经母细胞瘤发病机制的条件 ALK F1174L 突变小鼠模型。
DOI：
10.1002/dvg.23323
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Enomoto H.
中科院分区：
文献类型：
--
作者：
Ono S;Saito T;Terui K;Yoshida H;Enomoto H.
神经母细胞瘤是一种起源于交感神经节和肾上腺髓质的胚胎肿瘤，是最难治的儿科癌症之一。尽管在神经母细胞瘤中已经发现了多种基因变化，但它们如何影响其发病机制仍不清楚。最近的研究发现神经母细胞瘤中间变性淋巴瘤激酶（ALK）基因发生改变； ALK F1174L（密码子 1174 处的苯丙氨酸替换为亮氨酸）代表了这些体细胞突变中最常见的一种，并且与 MYCN 基因的扩增相关，而 MYCN 基因是生存不良的最可靠标记。我们对小鼠 Alklocus 进行了改造，使得 ALK F1174L 由其内源启动子表达，并且可以使用 Cre-loxP 系统以时空控制的方式进行诱导。尽管 ALK F1174L 的表达导致交感神经节祖细胞增殖增强并增加交感神经节的大小，但不足以引起神经母细胞瘤。然而，致死性神经母细胞瘤经常在共表达 ALK F1174L 和 MYCN 的小鼠中发生，即使在单独 MYCN 不会引起明显肿瘤的遗传背景下也是如此。这些数据表明 ALK F1174L 的生理表达显着增强 MYCN 体内的致癌能力。我们的条件突变小鼠为研究神经母细胞瘤的发病机制提供了一个有价值的平台。
Neuroblastoma, an embryonal tumor arising from the sympathetic ganglia and adrenal medulla, is among the most intractable pediatric cancers. Although a variety of genetic changes have been identified in neuroblastoma, how they contribute to its pathogenesis remains largely unclear. Recent studies have identified alterations of theanaplastic lymphoma kinase(ALK) gene in neuroblastoma; ALK F1174L (a phenylalanine‐to‐leucine substitution at codon 1174) represents one of the most frequent of these somatic mutations, and is associated with amplification of theMYCNgene, the most reliable marker for the poor survival. We engineered the mouseAlklocus so that ALK F1174L is expressed by its endogenous promoter and can be induced in a spatiotemporally controlled fashion using Cre‐loxP system. Although expression of ALK F1174L resulted in enhanced proliferation of sympathetic ganglion progenitors and increased the size of the sympathetic ganglia, it was insufficient to cause neuroblastoma. However, lethal neuroblastoma frequently developed in mice co‐expressing ALK F1174L and MYCN, even in a genetic background where MYCN alone does not cause overt tumors. These data reveal that physiological expression of ALK F1174L significantly potentiates the oncogenic ability of MYCN in vivo. Our conditional mutant mice provide a valuable platform for investigating the pathogenesis of neuroblastoma.