A Mouse Model for Human Gastrointestinal Stromal Tumor

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DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate: 1) mechanisms leading to the formation of gastrointestinal stromal tumor (GIST) and 2) the consequences of therapeutic intervention, by using a mouse model we have recently developed for this disease. The Kit receptor tyrosine kinase encoded at the murine W locus. Kit loss of function mutations result in major deficiencies in several major cell systems during embryogenesis and in the postnatal animal including gametogenesis, hematopoiesis, melanogenesis, and interstitial cells of Cajal (ICC) in the gastrointestinal tract. Normal Kit receptor mediated functions include cell proliferation, cell survival, cell adhesion, cell migration, secretory responses, and differentiation. In addition, in human neoplasia oncogenic activation of Kit is thought to have roles in gastro intestinal stromal tumors (GIST), mastocytosis/mast cell leukemia, acute myelogenous leukemia, and germ cell tumors. Activating Kit mutations are found in all of these neoplasms. Based on the finding of familial cases of GIST syndrome we have developed a mouse model for familial GIST syndrome by targeted mutation of the Kit receptor tyrosine kinase gene using a knock-in strategy. We now propose to use this mouse model to investigate mechanism of the development of GIST, to study the consequences of therapeutic intervention in mice with GIST and to elucidate mechanisms of signaling by oncogenetically activated Kit receptors. We furthermore propose to investigate the effect of the KitV558del mutation on the development of ICC networks during embryonic development and on embryonic heart development.