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Mastocytosis associated with a rare germline KIT K509I mutation displays a well- differentiated mast cell phenotype  Eunice Ching Chan, PhD, Yun Bai, MSc,

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Presentation on theme: "Mastocytosis associated with a rare germline KIT K509I mutation displays a well- differentiated mast cell phenotype  Eunice Ching Chan, PhD, Yun Bai, MSc,"— Presentation transcript:

1 Mastocytosis associated with a rare germline KIT K509I mutation displays a well- differentiated mast cell phenotype  Eunice Ching Chan, PhD, Yun Bai, MSc, Arnold S. Kirshenbaum, MD, Elizabeth R. Fischer, MA, Olga Simakova, PhD, Geethani Bandara, PhD, Linda M. Scott, CRNP, Laura B. Wisch, MSN, Daly Cantave, MSN, Melody C. Carter, MD, John C. Lewis, MD, Pierre Noel, MD, Irina Maric, MD, Alasdair M. Gilfillan, PhD, Dean D. Metcalfe, MD, Todd M. Wilson, DO  Journal of Allergy and Clinical Immunology  Volume 134, Issue 1, Pages e1 (July 2014) DOI: /j.jaci Copyright © Terms and Conditions

2 Fig 1 Clinicopathologic features of germline KIT K509I WDSM. A, Cutaneous presentation as an infant. B, Diffuse cutaneous presentation as an adult with comparison with typical KIT D816V urticarial pigmentosa. C, KIT and CD25 staining of bone marrow mast cells with comparison with typical KIT D816V morphology. D, Diagram of KIT and location of the heterozygous K509I mutation in relationship to GNNK splice site. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

3 Fig 2 Clinical reaction and response to imatinib. A, Erythematous rash exaggerated by the initiation of imatinib. B, Serum total tryptase levels on discontinuation and reinitiation of imatinib. C, Tryptase staining of a bone marrow biopsy specimen demonstrating mast cell involvement before and after imatinib. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

4 Fig 3 KIT K509I CD34+ progenitors display enhanced proliferation and develop into hypergranular HuMCs in the presence of SCF. A, Growth of K509I HuMCs in the presence of SCF. Data are means ± SEMs of 3 independent experiments performed in duplicate. B, Light microscopy with toluidine blue staining (×20 magnification) and EM. C, Side scatter (SSC) histogram. Results are representative of 3 experiments. *P < .05. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

5 Fig 4 SCF depletion affects KIT K509I HuMC proliferation, development, and survival. A and B, KIT K509I HuMC survival (Fig 4, A) and apoptosis (Fig 4, B) with various SCF concentrations. Data are means ± SEMs of 3 independent experiments performed in triplicate. C, Immunoblot of KIT phosphorylation before and after SCF stimulation. Results are representative of 3 experiments. D, SCF-independent KIT K509I HuMC growth. Data are means ± SEMs of 3 independent experiments performed in duplicate. E, Light microscopy with toluidine blue staining (×20 magnification). *P < .05, **P < .01, and ****P < Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

6 Fig 5 Activating potential of KIT K509I is dependent on the GNNK− isoform. A and B, MTT assay of transduced IC2 cells cultured in the presence (Fig 5, A) or absence (Fig 5, B) of SCF. Data are means ± SEMs of 3 independent experiments performed in triplicate. C and D, Growth and survival of transduced IC2 cells cultured in the presence (Fig 5, C) or absence (Fig 5, D) of SCF. Data are means ± SEMs of 2 independent experiments performed in duplicate. Control, Empty vector. *P < .05, **P < .01, ***P < .0005, and ****P < Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

7 Fig 6 KIT K509I HuMCs display enhanced antigen-mediated activation. A-F, β-Hexosaminidase release (Fig 6, A and B), PGD2 release (Fig 6, C and D), and intracellular Ca2+ flux (Fig 6, E and F) in the presence or absence of SCF. Data are means ± SEMs of 3 independent experiments performed in triplicate. Ca2+ flux represents an experiment performed in triplicate. G, FcεRI surface expression determined by means of flow cytometry. Results are representative of 3 experiments. H, CD226 immunoblotting of whole-cell lysates. Results are representative of 2 experiments. *P < .05, **P < .01, and ***P < Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

8 Fig 6 KIT K509I HuMCs display enhanced antigen-mediated activation. A-F, β-Hexosaminidase release (Fig 6, A and B), PGD2 release (Fig 6, C and D), and intracellular Ca2+ flux (Fig 6, E and F) in the presence or absence of SCF. Data are means ± SEMs of 3 independent experiments performed in triplicate. Ca2+ flux represents an experiment performed in triplicate. G, FcεRI surface expression determined by means of flow cytometry. Results are representative of 3 experiments. H, CD226 immunoblotting of whole-cell lysates. Results are representative of 2 experiments. *P < .05, **P < .01, and ***P < Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

9 Fig E1 Confirmation of the heterozygous germline KIT K509I mutation in various tissues and cell populations. Journal of Allergy and Clinical Immunology  , e1DOI: ( /j.jaci ) Copyright © Terms and Conditions

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