title: A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection.
abstract: In systemic mastocytosis (SM), clinical problems arise from factor-independent proliferation of mast cells (MCs) and the increased release of mediators by MCs, but no human cell line model for studying MC activation in the context of SM is available. We have created a stable stem cell factor (SCF) -dependent human MC line, ROSA(KIT WT), expressing a fully functional immunoglobulin E (IgE) receptor. Transfection with KIT D816V converted ROSA(KIT WT) cells into an SCF-independent clone, ROSA(KIT D816V), which produced a mastocytosis-like disease in NSG mice. Although several signaling pathways were activated, ROSA(KIT D816V) did not exhibit an increased, but did exhibit a decreased responsiveness to IgE-dependent stimuli. Moreover, NSG mice bearing ROSA(KIT D816V)-derived tumors did not show mediator-related symptoms, and KIT D816V-positive MCs obtained from patients with SM did not show increased IgE-dependent histamine release or CD63 upregulation. Our data show that KIT D816V is a disease-propagating oncoprotein, but it does not activate MCs to release proinflammatory mediators, which may explain why mediator-related symptoms in SM occur preferentially in the context of a coexisting allergy. ROSA(KIT D816V) may provide a valuable tool for studying the pathogenesis of mastocytosis and should facilitate the development of novel drugs for treating SM patients.
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre Nationale de la Recherche, Unité Mixte de Recherche 8113, Ecole Normale Supérieure de Cachan, Cachan, France;
authors.forename: Rosine
authors.initials: R
authors.lastname: Saleh
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre Nationale de la Recherche, Unité Mixte de Recherche 8113, Ecole Normale Supérieure de Cachan, Cachan, France; Department of Internal Medicine I, Division of Hematology and Hemostaseology, and.
authors.forename: Ghaith
authors.initials: G
authors.lastname: Wedeh
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre Nationale de la Recherche, Unité Mixte de Recherche 8113, Ecole Normale Supérieure de Cachan, Cachan, France;
authors.forename: Siham
authors.initials: S
authors.lastname: Bibi
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, and.
authors.forename: Irina
authors.initials: I
authors.lastname: Sadovnik
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatt
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria; Department of Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria;
authors.forename: Emir
authors.initials: E
authors.lastname: Hadzijusufovic
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre Nationale de la Recherche, Unité Mixte de Recherche 8113, Ecole Normale Supérieure de Cachan, Cachan, France;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Jeanningros
authors.affiliation: Flow Cytometry Core (Cytometry Pitié-Salpêtrière) CyPS, Université Pierre and Marie Curie, Paris, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Blanc
authors.affiliation: Laboratoire Central d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;
authors.forename: Magali
authors.initials: M
authors.lastname: Legarff-Tavernier
authors.affiliation: Laboratoire Central d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;
authors.forename: Elise
authors.initials: E
authors.lastname: Chapiro
authors.affiliation: Laboratoire Central d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;
authors.forename: Florence
authors.initials: F
authors.lastname: Nguyen-Khac
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre Nationale de la Recherche, Unité Mixte de Recherche 8113, Ecole Normale Supérieure de Cachan, Cachan, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Subra
authors.affiliation: Laboratoire Central d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;
authors.forename: Patrick
authors.initials: P
authors.lastname: Bonnemye
authors.affiliation: Aix-Marseille Université, INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Signaling, Hematopoiesis and Mechanism of Oncogenesis, Institut Paoli-Calmettes, and Centre Nationale de la Recherche Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, Marseille, France;
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.affiliation: Laboratoire d'Hématologie, Faculté de Pharmacie, Université Bordeaux Segalen, Bordeaux, France; and.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desplat
authors.affiliation: Laboratoire Central d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;
authors.forename: Hélène
authors.initials: H
authors.lastname: Merle-Béral
authors.affiliation: Department of Companion Animals and Horses, Small Animal Clinic, Internal Medicine, University of Veterinary Medicine Vienna, Vienna, Austria;
authors.forename: Michael
authors.initials: M
authors.lastname: Willmann
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée, Centre Nationale de la Recherche, Unité Mixte de Recherche 8113, Ecole Normale Supérieure de Cachan, Cachan, France; Laboratoire Central d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Arock
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D034721:Mastocytosis, Systemic / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D014162:Transfection
chemical_list: D007073:Immunoglobulin E; D019009:Proto-Oncogene Proteins c-kit