title: Mastocytosis cells bearing a c-kit activating point mutation are characterized by hypersensitivity to stem cell factor and increased apoptosis.
abstract: Mastocytosis is characterized by abnormal infiltration of mast cells into various organs. An activating mutation in c-kit, involving an A --> T substitution at nucleotide 2648 has recently been described in some patients with mastocytosis. We describe a 12-year-old girl with this mutation in her bone marrow cells at diagnosis with a myelodysplastic syndrome (MDS) without evidence of mastocytosis, and then in peripheral blood mononuclear cells 1 year later after the emergence of mastocytosis. The role of the c-Kit receptor and its ligand stem cell factor (SCF) in the pathogenesis of the disease was analysed in marrow cell clonogenic assays. We show that the genetic abnormalities in the patient resulted in factor-independent growth and hypersensitivity of primitive progenitors to SCF, with increased production of mast cells. Increased apoptosis and cluster formation, consistent with the myelodysplastic nature of the disorder, accompanied accumulation of abnormal cells with increasing concentrations of SCF.
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Research Institute, The Hospital for Sick Children and the University of Toronto, Toronto, Canada. yigal.dror@hotmail.com
authors.forename: Y
authors.initials: Y
authors.lastname: Dror
authors.forename: M
authors.initials: M
authors.lastname: Leaker
authors.forename: G
authors.initials: G
authors.lastname: Caruana
authors.forename: A
authors.initials: A
authors.lastname: Bernstein
authors.forename: M H
authors.initials: MH
authors.lastname: Freedman
mesh_terms: D017209:Apoptosis; D001856:Bone Marrow Examination; D002452:Cell Count; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D008415:Mastocytosis / Q000235:genetics* / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D019089:Stem Cell Factor / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit