title: Activation of KIT modulates the function of tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) in mast cells.
abstract: BACKGROUND
  Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation.
  
  
  METHODS
  We sought to further define the impact of TRAIL-Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis.
  
  
  RESULTS
  MC-specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1.
  
  
  CONCLUSIONS
  Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis.
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Förster
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: S P
authors.initials: SP
authors.lastname: Grotha
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Seeger
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rabenhorst
authors.affiliation: Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gehring
authors.affiliation: Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Raap
authors.affiliation: Inserm, U1068, CRCM, (Signaling, Hematopoiesis and Mechanism of Oncogenesis), Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Létard
authors.affiliation: Inserm, U1068, CRCM, (Signaling, Hematopoiesis and Mechanism of Oncogenesis), Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Dubreuil
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kashkar
authors.affiliation: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Walczak
authors.affiliation: Medical Faculty Carl Gustav Carus, Institute for Immunology, University of Technology Dresden, Dresden, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Roers
authors.affiliation: Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D008415:Mastocytosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D019089:Stem Cell Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D019009:Proto-Oncogene Proteins c-kit
keywords: KIT; apoptosis; mast cells; mastocytosis; tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R)