title: A new humanized in vivo model of KIT D816V+ advanced systemic mastocytosis monitored using a secreted luciferase.
abstract: Systemic mastocytosis are rare neoplasms characterized by accumulation of mast cells in at least one internal organ. The majority of systemic mastocytosis patients carry KIT D816V mutation, which activates constitutively the KIT receptor. Patient with advanced forms of systemic mastocytosis, such as aggressive systemic mastocytosis or mast cell leukemia, are poorly treated to date. Unfortunately, the lack of in vivo models reflecting KIT D816V+ advanced disease hampers pathophysiological studies and preclinical development of new therapies for such patients. Here, we describe a new in vivo model of KIT D816V+ advanced systemic mastocytosis developed by transplantation of the human ROSAKIT D816V-Gluc mast cell line in NOD-SCID IL-2R γ-/- mice, using Gaussia princeps luciferase as a reporter. Intravenous injection of ROSAKIT D816V-Gluc cells led, in 4 weeks, to engraftment in all injected primary recipient mice. Engrafted cells were found at high levels in bone marrow, and at lower levels in spleen, liver and peripheral blood. Disease progression was easily monitored by repeated quantification of Gaussia princeps luciferase activity in peripheral blood. This quantification evidenced a linear relationship between the number of cells injected and the neoplastic mast cell burden in mice. Interestingly, the secondary transplantation of ROSAKIT D816V-Gluc cells increased their engraftment capability. To conclude, this new in vivo model mimics at the best the features of human KIT D816V+ advanced systemic mastocytosis. In addition, it is a unique and convenient tool to study the kinetics of the disease and the potential in vivo activity of new drugs targeting neoplastic mast cells.
authors: Molecular and Cellular Oncology Research Group, LBPA CNRS UMR 8113, Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Siham
authors: S
authors: Bibi
authors: INSERM Unit U1170, Hématopoïèse normale et pathologique, Gustave Roussy Campus, Université Paris Sud Villejuif, France.
authors: Yanyan
authors: Y
authors: Zhang
authors: Molecular and Cellular Oncology Research Group, LBPA CNRS UMR 8113, Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Caroline
authors: C
authors: Hugonin
authors: INSERM Unit U1170, Hématopoïèse normale et pathologique, Gustave Roussy Campus, Université Paris Sud Villejuif, France.
authors: Mallorie Depond
authors: MD
authors: Mangean
authors: INSERM Unit U1170, Hématopoïèse normale et pathologique, Gustave Roussy Campus, Université Paris Sud Villejuif, France.
authors: Liang
authors: L
authors: He
authors: Molecular and Cellular Oncology Research Group, LBPA CNRS UMR 8113, Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Ghaith
authors: G
authors: Wedeh
authors: Laboratoire de Biochimie et Biologie Moléculaire, Inserm U942, Hôpital Lariboisière, AP-HP, Université Paris Diderot - Paris VII Paris, France.
authors: Jean-Marie
authors: JM
authors: Launay
authors: Neuro-oncology Research Group, Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherland.
authors: Sjoerd
authors: S
authors: Van Rijn
authors: Neuro-oncology Research Group, Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherland.|Neuroscience Center, Department of Neurology, Massachussetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA.
authors: Thomas
authors: T
authors: Würdinger
authors: INSERM Unit U1170, Hématopoïèse normale et pathologique, Gustave Roussy Campus, Université Paris Sud Villejuif, France.
authors: Fawzia
authors: F
authors: Louache
authors: Molecular and Cellular Oncology Research Group, LBPA CNRS UMR 8113, Ecole Normale Supérieure de Cachan, Cachan, France.|Laboratoire Central d'Hématologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie (UPMC) Paris VI, Paris, France.
authors: Michel
authors: M
authors: Arock
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008156:Luciferases / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000637:transplantation*; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D047428:Protein Kinase Inhibitors; D008156:Luciferases; D019009:Proto-Oncogene Proteins c-kit
keywords: KIT D816V mutant; NSG mice; ROSAKIT D816V cell line; advanced systemic mastocytosis; gluc reporter