NDLI: Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Chan, Eunice Ching Bai, Yun Kirshenbaum, Arnold S. Fischer, Elizabeth R. Simakova, Olga Bandara, Geethani Scott, Linda M. Wisch, Laura B. Cantave, Daly Carter, Melody C. Lewis, John C. Noel, Pierre Maric, Irina Gilfillan, Alasdair M. Metcalfe, Dean D. Wilson, Todd M.
Description	Country affiliation: Moldova Author Affiliation: Chan EC ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Bai Y ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Kirshenbaum AS ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Fischer ER ( Research Technologies Section, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Mont.); Simakova O ( Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md.); Bandara G ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Scott LM ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Wisch LB ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Cantave D ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Carter MC ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Lewis JC ( Division of Allergy, Asthma & Clinical Immunology, Mayo Clinic, Scottsdale, Ariz.); Noel P ( Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Ariz.); Maric I ( Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md.); Gilfillan AM ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Metcalfe DD ( Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.); Wilson TM ( 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.)
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. OBJECTIVES: 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. CONCLUSION: 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.
File Format	HTM / HTML
ISSN	00916749
e-ISSN	10976825
DOI	10.1016/j.jaci.2013.12.1090
Journal	Journal of Allergy and Clinical Immunology
Issue Number	1
Volume Number	134
Language	English
Publisher	Elsevier
Publisher Date	2014-07-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Immunology Germ-line Mutation Mast Cells Pathology Mastocytosis, Systemic Genetics Phenotype Proto-oncogene Proteins C-kit Alternative Splicing Cell Degranulation Drug Effects Cell Differentiation Cell Proliferation Cell Survival Cells, Cultured Gene Expression Immunology Stem Cell Factor Pharmacology Transduction, Genetic Research Support, N.i.h., Intramural
Content Type	Text
Resource Type	Article Case study
Subject	Immunology and Allergy Immunology

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