The ectoenzyme E-NPP3 (CD203c) has recently been identified as a novel activation-linked cell surface antigen on basophils. In the present study, we examined expression of CD203c on normal mast cells (MC) and bone marrow (bm) MC derived from 85 patients with systemic mastocytosis (SM), including cases with indolent SM (ISM, n=72), SM with associated clonal hematologic non-MC-lineage disease (SM-AHNMD, n=6), aggressive SM (ASM, n=3), and mast cell leukemia (MCL, n=4). Surface expression of CD203c was analyzed by multicolor flow cytometry. In patients with SM, bm MC expressed significantly higher amounts of CD203c compared to normal bm MC (median MFI in controls: 260 versus median MFI in SM: 516, p<0.05). Slightly lower amounts of CD203c were detected on MC in SM-AHNMD and ASM compared to ISM. To demonstrate CD203c expression in MC at the mRNA level, neoplastic MC were highly enriched by cell sorting, and were found to express CD203c mRNA in RT-PCR analysis. Cross-linking of the IgE receptor on MC resulted in a substantial upregulation of CD203c, whereas the KIT-ligand stem cell factor (SCF) showed no significant effects. In conclusion, CD203c is a novel activation-linked surface antigen on MC that is upregulated in response to IgE receptor cross-linking and is overexpressed on neoplastic MC in patients with SM.
LennertKParwareschMR. Mast cells and mast cell neoplasia: A review. Histopathology1979; 3:349–65.
2.
MetcalfeDD. Classification and diagnosis of mastocytosis: Current status. J Invest Dermatol1991; 96:2S–4S.
3.
ValentP. Biology, classification and treatment of human mastocytosis. Wien Klin Wochenschr1996; 108:385–97.
4.
ValentPAkinCSperrWRHornyHPArockMLechnerK. Diagnosis and treatment of systemic mastocytosis: State of the art. Br J Haematol2003; 122:695–717.
5.
AkinCMetcalfeDD. Systemic mastocytosis. Annu Rev Med2004; 55:419–32.
6.
EscribanoLAkinCCastellsMOrfaoAMetcalfeDD. Mastocytosis: Current concepts in diagnosis and treatment. Ann Hematol2002; 81:677–90.
7.
NagataHWorobecASOhCKChowdhuryBATannenbaumSSuzukiY. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci (USA)1995; 92:10560–4.
8.
LongleyBJTyrrellLLuSZMaYSLangleyKDingTG. Somatic c-kit activating mutation in urticaria pigmentosa and aggressive mastocytosis: Establishment of clonality in a human mast cell neoplasm. Nat Genet1996; 12:312–4.
9.
LongleyBJMetcalfeDDTharpMWangXTyrrellLLuSZ. Activating and dominant inactivating c-kit catalytic domain mutations in distinct forms of human mastocytosis. Proc Natl Acad Sci (USA)1999; 96:1609–14.
10.
Fritsche-PolanzRJordanJHFeixASperrWRSunder-PlassmannGValentP. Mutation analysis of C-KIT in patients with myelodysplastic syndromes without mastocytosis and cases of systemic mastocytosis. Br J Haematol2001; 113:357–64.
11.
Garcia-MonteroACJara-AcevedoMTeodosioCSanchezMLNunezRPradosA. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: A prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood2006; 108:2366–72.
12.
FuritsuTTsujimuraTTonoTIkedaHKitayamaHKoshimizuU. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of the c-kit product. J Clin Invest1993; 92:1736–44.
13.
ValentPHornyH-PEscribanoLLongleyBJLiCYSchwartzLB. Diagnostic criteria and classification of mastocytosis: A consensus proposal. Conference Report of “Year 2000 Working Conference on Mastocytosis”. Leuk Res2001; 25:603–25.
14.
ValentPHornyH-PLiCY. Mastocytosis (Mast cell disease). World Health Organization (WHO) Classification of Tumours. Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues. eds: JaffeESHarrisNLSteinHVardimanJW. 2001; 1:291–302.
15.
EscribanoLOrfaoADiaz-AgustinBDiaz-AgustinBCerveroCRiosA. Indolent systemic mast cell disease in adults: Immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood1998; 91:2731–6.
16.
EscribanoLDiaz-AgustinBBellasCNavalonRNunezRSperrWR. Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis. Leuk Res2001; 25:563–70.
17.
Nunez-LopezREscribanoLSchernthanerGHPradosAGonzalezR RodriguezAgustinB Diaz. Overexpression of complement receptors and related antigens on the surface of bone marrow mast cells in patients with systemic mastocytosis. Br J Haematol2003; 120:257–65.
18.
SchernthanerGHJordanJHGhannadanMAgisHBevecDNunezR. Expression, epitope analysis, and functional role of the LFA-2 antigen detectable on neoplastic mast cells. Blood2001; 98:3784–92.
19.
ValentPSchernthanerGHSperrWRFritschGAgisHWillheimM. Variable expression of activation-linked surface antigens on human mast cells in health and disease. Immunol Rev2001; 179:74–81.
20.
KnolEFMulFPJJansenHCalafatJRoosD. Monitoring human basophil activation via CD63 monoclonal antibody 435. J Allergy Clin Immunol1991; 88:328–38.
21.
BühringH-JSimmonsPJPudneyMMullerRJarrossayDAgthovenA. The monoclonal antibody 97A6 defines a novel surface antigen expressed on human basophils and their multi- and unipotent progenitors. Blood1999; 94:2343–56.
22.
BühringHJSeiffertMGiesertCMarxerAKanzLValentP. The basophil activation marker defined by antibody 97A6 is identical with ectonucleotide pyrophosphatase/phosphodiesterase 3 (E-NPP3; CD203c). Blood2001; 97:3303–5.
23.
HauswirthAWNatterSGhannadanMMajlesiYSchernthanerGHSperrWR. Recombinant allergens promote expression of CD203c on basophils in sensitized individuals. J Allergy Clin Immunol2002; 110:102–9.
24.
GhannadanMHauswirthAWSchernthanerGHMüllerMRKlepetkoWSchatzlG. Detection of novel CD antigens on the surface of human mast cells and basophils. Int Arch Allergy Immunol2002; 127:299–307.
25.
BühringHJStrebleAValentP. The basophilspecific ectoenzyme E-NPP3 (CD203c) as a marker for cell activation and allergy diagnosis. Int Arch Allergy Immunol2004; 133:317–29.
26.
ValentPAshmanLKHinterbergerWEckersbergerFMajdicOLechnerK. Mast cell typing: Demonstration of a distinct hematopoietic cell type and evidence for immunophenotypic relationship to mononuclear phagocytes. Blood1989; 73:1778–85.
27.
SotlarKHornyHPSimonitschIKrokowskiMAichbergerKJMayerhoferM. CD25 indicates the neoplastic phenotype of mast cells: A novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol2004; 28:1319–25.
28.
ButterfieldJHWeilerDDewaldGGleichGJ. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res1988; 12:345–55.
29.
SillaberCStroblHBevecDAshmanLKButterfieldJHLechnerK. IL-4 regulates c-kit proto-oncogene product expression in human mast and myeloid progenitor cells. J Immunol1991; 147:4224–8.
30.
MirkinaISchweighofferTKricekF. Inhibition of human cord blood-derived mast cell responses by anti-Fc epsilon RI mAb 15/1 versus anti-IgE Omalizumab. Immunol Lett2007; 109:120–8.
31.
EscribanoLDiaz-AgustinBLopezALopezR NunezGarcia-MonteroAAlmeidaJ. Spanish Network on Mastocytosis (REMA). Immunophenotypic analysis of mast cells in mastocytosis: When and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry B Clin Cytom2004; 58:1–8.
32.
WimazalFKrauthMTValesABöhmAAgisHSonneckK. Immunohistochemical detection of vascular endothelial growth factor (VEGF) in the bone marrow in patients with myelodysplastic syndromes: Correlation between VEGF expression and the FAB category. Leuk Lymphoma2006; 47:451–60.
33.
ValentPAkinCEscribanoLFodingerMHartmannKBrockowK. Standards and standardization in mastocytosis: Consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest2007; 37:435–53.
