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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Perry, Mary Ellen
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Sloan-Kettering Institute for Cancer Research
New York
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Seifert, Adrian M; Zeng, Shan; Zhang, Jennifer Q et al. (2017) PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors. Clin Cancer Res 23:454-465
Bosbach, Benedikt; Rossi, Ferdinand; Yozgat, Yasemin et al. (2017) Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc Natl Acad Sci U S A 114:E8448-E8457
Buono, Mario; Facchini, Raffaella; Matsuoka, Sahoko et al. (2016) A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat Cell Biol 18:157-67
Ran, Leili; Sirota, Inna; Cao, Zhen et al. (2015) Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth. Cancer Discov 5:304-15
Deshpande, Shayu; Bosbach, Benedikt; Yozgat, Yasemin et al. (2013) KIT receptor gain-of-function in hematopoiesis enhances stem cell self-renewal and promotes progenitor cell expansion. Stem Cells 31:1683-95
Cavnar, Michael J; Zeng, Shan; Kim, Teresa S et al. (2013) KIT oncogene inhibition drives intratumoral macrophage M2 polarization. J Exp Med 210:2873-86
Italiano, Antoine; Chen, Junwei; Zhang, Lei et al. (2012) Patterns of deregulation of insulin growth factor signalling pathway in paediatric and adult gastrointestinal stromal tumours. Eur J Cancer 48:3215-22
Chen, Junwei; Guo, Tianhua; Zhang, Lei et al. (2012) CD133 and CD44 are universally overexpressed in GIST and do not represent cancer stem cell markers. Genes Chromosomes Cancer 51:186-95
Bosbach, Benedikt; Deshpande, Shayu; Rossi, Ferdinand et al. (2012) Imatinib resistance and microcytic erythrocytosis in a KitV558ýý;T669I/+ gatekeeper-mutant mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci U S A 109:E2276-83
Balachandran, Vinod P; Cavnar, Michael J; Zeng, Shan et al. (2011) Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 17:1094-100

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