title: Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase.
abstract: 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 KitV558Delta/+ 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 KitV558Delta/+ 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.
authors.affiliation: Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10021, USA.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Sommer
authors.forename: Valter
authors.initials: V
authors.lastname: Agosti
authors.forename: Imke
authors.initials: I
authors.lastname: Ehlers
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.forename: Selim
authors.initials: S
authors.lastname: Corbacioglu
authors.forename: Judith
authors.initials: J
authors.lastname: Farkas
authors.forename: Malcolm
authors.initials: M
authors.lastname: Moore
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D018390:Gene Targeting; D006579:Heterozygote; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; D019009:Proto-Oncogene Proteins c-kit