title: Mast cell hyperplasia, B-cell malignancy, and intestinal inflammation in mice with conditional expression of a constitutively active kit.
abstract: Signaling through the receptor tyrosine kinase kit controls proliferation and differentiation of hematopoietic precursor cells and mast cells. Somatic point mutations of the receptor that constitutively activate kit signaling are associated with mastocytosis and various hematopoietic malignancies. We generated a Cre/loxP-based bacterial artificial chromosome transgenic mouse model that allows conditional expression of a kit gene carrying the kitD814V mutation (the murine homolog of the most common mutation in human mastocytosis, kitD816V) driven by the kit promoter. Expression of the mutant kit in cells of adult mice, including hematopoietic precursors, caused severe mastocytosis with 100% penetrance at young age frequently associated with additional hematopoietic (mostly B lineage-derived) neoplasms and focal colitis. Restriction of transgene expression to mature mast cells resulted in a similar mast cell disease developing with slower kinetics. Embryonic expression led to a hyperproliferative dysregulation of the erythroid lineage with a high rate of perinatal lethality. In addition, most adult animals developed colitis associated with mucosal mast cell accumulation. Our findings demonstrate that the effects of constitutive kit signaling critically depend on the developmental stage and the state of differentiation of the cell hit by the gain-of-function mutation.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gerbaulet
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.forename: Julia
authors.initials: J
authors.lastname: Scholten
authors.forename: Katrin
authors.initials: K
authors.lastname: Peschke
authors.forename: Sebastian
authors.initials: S
authors.lastname: Drube
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Horny
authors.forename: Thomas
authors.initials: T
authors.lastname: Kamradt
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.forename: Claudia
authors.initials: C
authors.lastname: Waskow
authors.forename: Karin
authors.initials: K
authors.lastname: Hartmann
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003092:Colitis / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000473:pathology; D008415:Mastocytosis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
chemical_list: D017931:DNA Primers; D019009:Proto-Oncogene Proteins c-kit