Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase
Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase
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DOI：
10.1073/pnas.1037763100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Besmer, P
中科院分区：
文献类型：
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作者：
Sommer, G;Agosti, V;Besmer, P
在躯体胃肠道（GI）间质瘤（gist）和肥大细胞增生症中发现了致癌Kit突变。基于在人类家族性GIST综合征病例中发现的突变，通过敲入策略将Kit外显子11激活突变引入小鼠基因组，建立了用于研究Kit在肿瘤发生中的组成性激活的小鼠模型。杂合突变试剂盒(V558Delta)/+小鼠出现疾病症状并最终死于胃肠道病理。在整个胃肠道的肌丛内可见明显的kit阳性细胞斑片状增生。在高外显率的突变小鼠的盲肠中观察到与人类gist难以区分的肿瘤病变。背侧皮肤肥大细胞数量增加。因此，Kit(V558Delta)/+小鼠可复制人类家族性gist，并可作为研究Kit在肿瘤发生中的作用和机制的模型。重要的是，这些结果表明，组成型Kit信号传导是诱导间质间质干细胞和Cajal间质细胞增生的关键和充分条件。
Oncogenic Kit mutations are found in somatic gastrointestinal (GI) stromal tumors (GISTs) and mastocytosis. A mouse model for the study of constitutive activation of Kit in oncogenesis has been produced by a knock-in strategy introducing a Kit exon 11-activating mutation into the mouse genome based on a mutation found in a case of human familial GIST syndrome. Heterozygous mutant Kit(V558Delta)/+ mice develop symptoms of disease and eventually die from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells is evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. in addition, mast cell numbers in the dorsal skin were increased. Therefore Kit(V558Delta)/+ mice reproduce human familial GISTs, and they may be used as a model for the study of the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrate that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal.