title: Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype.
abstract: BACKGROUND
  Mastocytosis associated with germline KIT activating mutations is exceedingly rare. We report the unique clinicopathologic features of a patient with systemic mastocytosis caused by a de novo germline KIT K509I mutation.
  
  
  OBJECTIVE
  We sought to investigate the effect of the germline KIT K509I mutation on human mast cell development and function.
  
  
  METHODS
  Primary human mast cells derived from CD34(+) peripheral blood progenitors were examined for growth, development, survival, and IgE-mediated activation. In addition, a mast cell transduction system that stably expressed the KIT K509I mutation was established.
  
  
  RESULTS
  KIT K509I biopsied mast cells were round, CD25(-), and well differentiated. KIT K509I progenitors cultured in stem cell factor (SCF) demonstrated a 10-fold expansion compared with progenitors from healthy subjects and developed into mature hypergranular mast cells with enhanced antigen-mediated degranulation. KIT K509I progenitors cultured in the absence of SCF survived but lacked expansion and developed into hypogranular mast cells. A KIT K509I mast cell transduction system revealed SCF-independent survival to be reliant on the preferential splicing of KIT at the adjacent exonic junction.
  
  
  CONCLUSIONS
  Germline KIT mutations associated with mastocytosis drive a well-differentiated mast cell phenotype distinct to that of somatic KIT D816V disease, the oncogenic potential of which might be influenced by SCF and selective KIT splicing.
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Eunice Ching
authors.initials: EC
authors.lastname: Chan
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Kirshenbaum
authors.affiliation: Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Mont.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Fischer
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md.
authors.forename: Olga
authors.initials: O
authors.lastname: Simakova
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Geethani
authors.initials: G
authors.lastname: Bandara
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Scott
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Wisch
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Daly
authors.initials: D
authors.lastname: Cantave
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Melody C
authors.initials: MC
authors.lastname: Carter
authors.affiliation: Division of Allergy, Asthma & Clinical Immunology, Mayo Clinic, Scottsdale, Ariz.
authors.forename: John C
authors.initials: JC
authors.lastname: Lewis
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Ariz.
authors.forename: Pierre
authors.initials: P
authors.lastname: Noel
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: twilson@mail.nih.gov.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Wilson
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D015550:Cell Degranulation / Q000187:drug effects; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D018095:Germ-Line Mutation; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D034721:Mastocytosis, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D019089:Stem Cell Factor / Q000494:pharmacology; D014161:Transduction, Genetic
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit
keywords: K509I; KIT; germline; mast cells; mastocytosis; well differentiated