A mouse model for human gastrointestinal stromal tumor

说明(申请人提供)：KIT受体在几个细胞系统中发挥关键作用，包括造血、色素系统、配子发生和胃肠道的起搏细胞。Kit受体介导的正常功能包括细胞增殖、细胞存活、细胞黏附、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、急性髓系白血病、一小部分黑色素瘤和一组生殖细胞肿瘤中起作用。KIT受体的功能是通过激酶激活、受体自身磷酸化以及与各种信号分子和信号级联反应来介导的。受体酪氨酸激酶如Kit如何在胚胎发育和出生后的不同细胞类型中介导不同的细胞反应；以及不同细胞类型的致癌转化产生癌症的要求是什么。我们培育出的小鼠含有Kit受体基因的敲入点突变、功能丧失和功能获得突变，这些突变阻止了不同的信号级联反应，或在不同的细胞类型中提供Kit的致癌激活并推动肿瘤的发生。大多数胃肠道间质瘤表达KIT受体酪氨酸激酶，致癌KIT信号驱动GIST肿瘤的发生。GIST发病的主要遗传事件被认为是KIT基因的功能获得突变，偶尔也可能是PDGFRα基因的突变。家族性GIST综合征患者携带生殖系试剂盒功能获得突变。家族性GIST中遗传试剂盒功能突变的观察为我们建立这种疾病的小鼠模型提供了理论基础。通过使用敲入策略，在一个家族性GIST病例中发现的Kit-V558缺失突变被引入到小鼠基因组中。值得注意的是，杂合突变的KitV558/+小鼠为人类家族性GIST提供了一个忠实的小鼠模型，并证明了结构性KIT信号对于GIST的诱导和Cajal间质细胞的增殖是必要和充分的(Sommer等，2003)。这些GIST小鼠为研究KIT受体GIST在体内的致癌作用和靶向药物干预研究提供了一个极好的工具。这项建议的总体目标有两个，1)继续我们对Kit驱动的GIST肿瘤发生和肿瘤进展机制的研究，2)探索治疗伊马替尼敏感和耐药的GIST的新策略。

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.