Mast cells express c-kit and proliferate after exposure to c-kit ligand. Mutations in c-kit may enhance or interfere with the ability of the c-kit receptor to initiate the signal transduction events that result in cell proliferation. We thus screened the peripheral blood mononuclear cells of patients with indolent mastocytosis (IM), mastocytosis with an associated hematologic disorder (MAHD), aggressive mastocytosis (AM), solitary mastocytoma, and CMML unassociated with mastocytosis for a mutation in the c-kit receptor using single strand conformational polymorphism (SSCP) analysis. In our initial analysis (Nagata et. al, PNAS, USA 1995, 92:10560-10564) 4 out of 4 patients with MAHD with predominantly myelodysplastic features had an A~T substitution at nucleotide 2468 of c-kit mRNA that causes an Asp-816~Val substitution in the catalytic domain of the c-kit receptor. This mutation was not identified in other categories of mastocytosis or in 67 of 67 controls. These findings were confirmed in the genomic DNA of a patient with MAHD. Pedigree analysis of 2 families suggests that the mutation is somatic. Screening of additional mastocytosis patients (46 total) has resulted in the following findings: 100% of patients with MAHD have the Asp(816)Val mutation in the c-kit receptor (n=8), 0% of patients with urticaria pigmentosa alone have this mutation (n=6), and 20% of patients with IM (6/30) have the Asp(816)Val mutation. Of this latter group of IM patients, disease was characterized by more severe manifestations and clinical features suggestive of early myelodysplastic or myeloproliferative syndromes. These patients more commonly had osteosclerotic bone involvement, a clinical feature primarily seen in the patients with MAHD, along with immunoglobulinopathies and peripheral blood abnormalities.
| Akin, Cem; Valent, Peter; Metcalfe, Dean D (2010) Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol 126:1099-104.e4 |
| Kulka, Marianna; Metcalfe, Dean D (2010) Isolation of tissue mast cells. Curr Protoc Immunol Chapter 7:Unit 7.25 |
| Lahortiga, Idoya; Akin, Cem; Cools, Jan et al. (2008) Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion. Haematologica 93:49-56 |
| Simons, F E R; Frew, A J; Ansotegui, I J et al. (2008) Practical allergy (PRACTALL) report: risk assessment in anaphylaxis. Allergy 63:35-7 |
| Peavy, Richard D; Metcalfe, Dean D (2008) Understanding the mechanisms of anaphylaxis. Curr Opin Allergy Clin Immunol 8:310-5 |
| Simons, F Estelle R; Frew, Anthony J; Ansotegui, Ignacio J et al. (2007) Risk assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol 120:S2-24 |
| Valent, P; Akin, C; Escribano, L et al. (2007) Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 37:435-53 |
| Jensen, Bettina M; Metcalfe, Dean D; Gilfillan, Alasdair M (2007) Targeting kit activation: a potential therapeutic approach in the treatment of allergic inflammation. Inflamm Allergy Drug Targets 6:57-62 |
| Carter, Melody C; Robyn, Jamie A; Bressler, Peter B et al. (2007) Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol 119:1550-1 |
| Akin, Cem; Scott, Linda M; Kocabas, Can N et al. (2007) Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with ""idiopathic"" anaphylaxis. Blood 110:2331-3 |
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