Clonal cytogenetic abnormalities similar to those observed in other haematological neoplasms are demonstrable in a proportion of patients with systemic mastocytosis and in a smaller proportion of adults with urticaria pigmentosa without apparent systemic disease. These clonal abnormalities are not likely to represent the primary event in mast cell neoplasms. Although no recurrent cytogenetic abnormalities specific for mastocytosis have yet been recognized, the majority of cases display one of several mutations in c-KIT, the gene encoding the receptor for stem cell factor. That most commonly observed is the Asp816Val mutation, which permits proliferation independent of growth factors. c-KIT mutations may play a significant role in the biology of mast cell malignancies, although other mutations may be needed for a malignant phenotype.

Keywords:
Cytogenetics, Molecular genetics, Mastocytosis, Urticaria pigmentosa, c-KIT
1.
Jaffe ES, Harris NL, Stein H, Vardiman J: The World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, 2001.
2.
Lishner M, Confino-Cohen R, Mekori YA, Feigin M, Manor Y, Goldberg A, Ravid M, Amiel M: Trisomies 9 and 8 detected by fluorescence in situ hybridization in patients with systemic mastocytosis. J Allergy Clin Immunol 1996;98:199–204.
3.
Swolin B, Rodjer S, Roupe G: Cytogenetic studies in patients with mastocytosis. Cancer Genet Cytogenet 2000;120:131–135.
4.
Swolin B, Rodjer S, Roupe G: Cytogenetic studies and in vitro colony growth in patients with mastocytosis. Blood 1987;70:1928–1932.
5.
Travis WD, Li C-Y, Yam T, Bergstrahl EJ, Swee RG: Significance of systemic mast cell disease with associated haematologic diagnosis. Cancer 1988;62:965–972.
6.
Bauchinger M, Mezger J: A case of malignant mastocytosis with near-haploid, near-diploid, and polyploid cells in the bone marrow. Cancer Genet Cytogenet 1990;48:13–21.
7.
Mezger J, Permanetter W, Gerhartz H, Bartl R, Bauchinger M, Schmetzer H, Sauer H: Philadelphia chromosome-negative acute hemopoietic malignancy: Ultrastructural, cytochemical and immunocytochemical evidence of mast cell and basophil differentiation. Leukemia Res 1990;14:169–175.
8.
Shekter-Levin S, Ball E, Swerdlow SH, Li WV, Kapadia SB, Sherer ME, Wald N, Gollin SM: A near-haploid marrow in systemic mast cell disease: Is it characteristic of the disease or an incidental finding? Cancer Genet Cytogenet 1998;103:124–129.
9.
Beghini A, Cairoli R, Morra E, Larizza L: In vivo differentiation of mast cells from AML M2 blasts carrying a novel activating ligand-independent c-KIT mutation. Br J Haematol 1998;102:13.
10.
Wong KF, Chan JK, Chan JC, Kwong YL, Ma SK, Chow TC: Concurrent acute myeloid leukemia and systemic mastocytosis. Am J Hematol 1991;38:243–244.
11.
Jordan JH, Walchshofer S, Jurecka W, Mosberger I, Sperr WR, Wolff K, Chott A, Buhring HJ, Lechner K, Horny HP, Valent P: Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: Evidence for expression of CD2, CD117/Kit, and bcl-x(L). Hum Pathol 2001;32:545–552.
12.
Escribano L, Orfao A, Villarrubia J, Martin F, Madruga JI, Cuevas M, Velasco JL, Rios A, San Miguel JF: Sequential immunophenotypic analysis of mast cells in a case of systemic mast cell disease evolving to a mast cell leukemia. Cytometry 1997;30:98–102.
13.
Nocka K, Majumder S, Chabot B, Ray P, Cervone M, Bernstein A, Besmer P: Expression of c-kit gene products in known cellular targets of W mutations in normal and W mutant mice – evidence for an impaired c-kit kinase in mutant mice. Genes Dev 1989;3:816–826.
14.
Mekori YA, Oh CK, Metcalfe DD: IL-3-dependent murine mast cells undergo apoptosis on removal of IL-3. Prevention of apoptosis by c-kit ligand. J Immunol 1993;151:3775–3784.
15.
Bain BJ: Systemic mastocytosis and other mast cell neoplasms. Br J Haematol 1999;106:9–17.
16.
Akin C, Schwartz LB, Kitoh T, Obayashi H, Worobec AS, Scott LM, Metcalfe DD: Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: Relationships to disease severity and bone marrow pathology. Blood 2000;96:1267–1273.
17.
Akin C, Kirshenbaum AS, Semere T, Worobec AS, Scott LM, Metcalfe DD: Analysis of the surface expression of c-kit and occurrence of the c-kit Asp816Val activating mutation in T cells, B cells and myelomonocytic cells in patients with mastocytosis. Exp Hematol 2000;28:140–147.
18.
Takahashi N, Miura I, Saitoh K, Miura AB: Lineage involvement of stem cells bearing the philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood 1998;92:4758–4763.
19.
Longley BJ Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, Heitjan D, Ma Y: Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci USA 1999;96:1609–1614.
20.
Kitayama H, Tsujimura T, Matsumura I, Oritani K, Ikeda H, Ishikawa J, Okabe M, Suzuki M, Yamamura K, Matsuzawa Y, Kitamura Y, Kanakura Y: Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase. Blood 1996;88:995–1004.
21.
Tsujimura T, Hashimoto K, Kitayama H, Ikeda H, Sugahara H, Matsumura I, Kaisho T, Terada N, Kitamura Y, Kanakura YZ: Activating mutation in the catalytic domain of c-kit elicits hematopoietic transformation by receptor self-association not at the ligand-induced dimerization site. Blood 1999;93:1319–1329.
22.
Piao X, Paulson R, van der Geer P, Pawson T, Bernstein A: Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. Proc Natl Acad Sci USA 1996;93:14665–14669.
23.
Chian R, Young S, Danilkovitch-Miagkova A, Ronnstrand L, Leonard E, Ferrao P, Ashman L, Linnekin D: PI3 kinase mediates transformation of hematopoietic cells by the V816 c-kit mutant. Exp Haematol 2000;28:1491.
24.
Ashman LK, Ferrao P, Cole SR, Cambareri AC: Effects of mutan c-kit in early myeloid cells. Leuk Lymphoma 2000;37:233–243.
25.
Nilsson G, Miettinen U, Ishizaka T, Ashman LK, Irani AM, Schwartz LB: Interleukin-4 inhibits the expression of Kit and tryptase during stem cell factor-dependent development of human mast cells from fetal liver cells. Blood 1994;84:1519–1527.
26.
Khurana Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA: The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 1997;337:1720–1725.
27.
Daley T, Metcalfe DD, Akin C: Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin. Blood 2001;98:880–882.
28.
Lewis JP, Welborn JL, Meyers FJ, Levy NB, Roschak T: Mast cell disease followed by leukemia with cloncal evolution. Leuk Res 1987;11:769–773.
29.
Zhang Y, Schlegelberger B, Weber-Matthiesen K, Grote W, Bartels H: Translocation [X;8][q2?6;q21.3] in a case of systemic mastocytosis. Cancer Genet Cytogenet 1994;78:236–241.
30.
Travis WD, Li C-Y, Hoagland HC, Travis LB, Banks PM: Mast cell leukemia: Report of a case and review of the literature. Mayo Clinic Proc 1986;61:957–966.
31.
Buttner C, Henz BM, Welker P, Sepp NT, Grabbe J: Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: A possible explanation for divergent clinical behavior. J Invest Dermatol 1998;111:1227–1231.
32.
Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, Metcalfe DD: 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;92:10560–10564.
33.
Nagata H, Okada T, Worobec AS, Semere T, Metcalfe DD: c-kit mutation in a population of patients with mastocytosis. Int Arch Allergy Immunol 1997;113:184–186.
34.
Worobec AS, Semere T, Nagata H, Metcalfe DD: Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with mastocytosis. Cancer 1998;83:2120–2129.
35.
Sato-Matsumura KC, Matsumura T, Koizumi H, Sato H, Nagashima K, Ohkawara A: Analysis of c-kit exon 11 and exon 17 of urticaria pigmentosa that occurred in monozygotic twin sisters. Br J Dermatol 1999;140:1130–1132.
36.
Pullarkat VA, Pullarkat ST, Calverley DC, Brynes RK: Mast cell disease associated with acute myeloid leukemia: Detection of a new c-kit mutation Asp816His. Am J Hematol 2000;65:307–309.
37.
Afonja O, Amorosi E, Ashman L, Takeshita K: Multilineage involvement and erythropoietin-‘independent’ erythroid progenitor cells in a patient with systemic mastocytosis. Ann Hematol 1998;77:183–186.
38.
Sperr WR, Walchshofer S, Horny HP, Fodinger M, Simonitsch I, Fritsche-Polanz R, Schwarzinger I, Tschachler E, Sillaber C, Hagen W, Geissler K, Chott A, Lechner K, Valent P: Systemic mastocytosis associated with acute myeloid leukaemia: Report of two cases and detection of the c-kit mutation Asp-816 to Val. Br J Haematol 1998;103:740–749.
39.
Sotlar K, Marafioti T, Griesser H, Theil J, Aepinus C, Jaussi R, Stein H, Valent P, Horny HP: Detection of c-kit mutation Asp816 to Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukaemia. Mol Pathol 2000;53:188–193.
40.
Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E, Mecucci C: c-kit mutations in core binding factor leukemias. Blood 2000;95:726–727.
41.
Pignon JM, Giraudier S, Duquesnoy P, Jouault H, Imbert M, Vainchenker W, Vernant JP, Tulliez M: A new c-kit mutation in a case of aggressive mast cell disease. B J Haematol 1997;96:374–376.
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2002
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