A mouse model for human gastrointestinal stromal tumor

描述（由申请人提供）：KIT受体在几个细胞系统中起关键作用，包括造血、色素系统、配子发生和胃肠道起搏器细胞。正常Kit受体介导的功能包括细胞增殖、细胞存活、细胞粘附、细胞迁移、分泌反应和分化。在人类肿瘤中，Kit的致癌激活在胃肠道间质瘤、肥大细胞增多症/肥大细胞白血病、急性骨髓性白血病、一小部分黑色素瘤和一小部分生殖细胞肿瘤中起作用。Kit受体的功能由激酶激活、受体自磷酸化以及与各种信号分子和信号级联的关联介导。受体酪氨酸激酶（如Kit）如何在胚胎发育和出生后的动物中介导不同细胞类型的不同细胞反应；不同细胞类型的致癌转化产生癌症的条件是什么。我们已经生产出含有敲入点突变、Kit受体基因功能丧失和功能突变的小鼠，这些突变阻断了不同的信号级联反应，或者在不同的细胞类型中提供Kit的致癌激活并驱动肿瘤发生。大多数胃肠道间质肿瘤表达KIT受体酪氨酸激酶，而致瘤性KIT信号通路驱动GIST肿瘤发生。GIST发病机制的主要遗传事件被认为是KIT基因或偶尔的PDGFR α基因的功能获得突变。家族性GIST综合征患者携带种系KIT功能获得突变。家族性GIST中功能突变的遗传性KIT获得的观察为我们开发这种疾病的小鼠模型提供了理论依据。通过使用敲入策略，在家族性GIST病例中发现的Kit-V558缺失突变被引入小鼠基因组。值得注意的是，杂合突变体KitV558 /+小鼠为人类家族性GIST提供了忠实的小鼠模型，并证明了组成型KIT信号对于诱导GIST和Cajal间质细胞增生是必要和充分的（Sommer et al., 2003）。这些GIST小鼠为研究KIT受体在体内胃肠道间质瘤发生中的作用和靶向药物干预研究提供了很好的工具。本提案的总体目标是双重的，1)继续我们对Kit驱动的GIST肿瘤发生和肿瘤进展的机制的研究，2)研究伊马替尼敏感和伊马替尼耐药GIST的新治疗策略。

DESCRIPTION (provided by applicant): The KIT receptor has critical roles in several cell systems including hematopoiesis, the pigmentary system, gametogenesis, and in pacemaker cells of the gastrointestinal tract. Normal Kit receptor mediated functions include cell proliferation, cell survival, cell adhesion, cell migration, secretory responses and differentiation. In human neoplasia oncogenic activation of Kit has roles in gastrointestinal stromal tumors, mastocytosis/mast cell leukemia, acute myelogenous leukemia, a minor subset of melanomas and a subset of germ cell tumors. Kit receptor functions are mediated by kinase activation, receptor autophosphorylation and association with various signaling molecules and signaling cascades. How do receptor tyrosine kinases such as Kit mediate distinct cellular responses in different cell types during embryonic development and in the postnatal animal; and what are the requirements for oncogenic transformation in different cell types to produce cancer. We have produced mice containing knock-in point mutations, loss of function and gain of function mutations in the Kit receptor gene in mice which block distinct signaling cascades or which provide for oncogenic activation of Kit in distinct cell types and driving oncogenesis. Most gastrointestinal stromal tumors express the KIT receptor tyrosine kinase, and oncogenic KIT signaling drives GIST tumorigenesis. The principal genetic events responsible for the pathogenesis of GIST are thought to be gain-of-function mutations in the KIT gene or occasionally in the PDGFR alpha gene. Patients with familial GIST syndrome carry a germline KIT gain-of-function mutation. The observation of inherited KIT gain of function mutations in familial GIST provided us with a rationale for developing mouse models for this disease. By using a knock-in strategy, the Kit-V558 deletion mutation found in a familial GIST case was introduced into the mouse genome. Remarkably, heterozygous mutant KitV558 /+ mice provide a faithful mouse model for human familial GIST, and demonstrated that constitutive KIT signaling is necessary and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal (Sommer et al., 2003). These GIST mice provide an excellent tool to study the role of the KIT receptor GIST oncogenesis in vivo and for studies of targeted pharmacological intervention. The overall objective of this proposal is twofold, 1) to continue our investigations into the mechanism of Kit driven GIST oncogenesis and tumor progression, and 2) to investigate new treatment strategies for imatinib sensitive and imatinib resistant GIST.