KIT is a receptor tyrosine kinase that is functionally relevant for hematopoiesis, mast cell development and function, gametogenesis and melanogenesis. Normal KIT signaling requires binding to stem cell factor, and PI3K-Akt is one of the putative effector pathways. In humans, germline loss-of-function KIT mutations have been associated with piebaldism – an autosomal dominant condition characterized by depigmented patches of skin and hair. Gain-of-function KIT mutations are usually acquired and have been associated with myeloid malignancies including core binding factor acute myeloid leukemia and systemic mastocytosis (SM), germ cell tumors, gastrointestinal stromal tumors and sinonasal T cell lymphomas. KIT D816V is the most prevalent KIT mutation in mast cell disease and occurs in more than 90% of the cases that fulfill the World Health Organization diagnostic criteria for SM. However, its precise pathogenetic contribution is not well understood. In clinical practice, SM is considered either indolent or aggressive depending on the respective absence or presence of symptomatic target organ dysfunction aside from skin disease. In general, conventional therapy for SM is suboptimal, and efforts are under way to develop and employ small molecule drugs that target mutant KIT.

Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A: Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 1987;6:3341–3351.
d’Auriol L, Mattei MG, Andre C, Galibert F: Localization of the human c-kit protooncogene on the q11-q12 region of chromosome 4. Hum Genet 1988;78:374–376.
Roskoski R Jr: Structure and regulation of Kit protein-tyrosine kinase – the stem cell factor receptor. Biochem Biophys Res Commun 2005;338:1307–1315.
Geissler EN, Liao M, Brook JD, Martin FH, Zsebo KM, Housman DE, Galli SJ: Stem cell factor (SCF), a novel hematopoietic growth factor and ligand for c-kit tyrosine kinase receptor, maps on human chromosome 12 between 12q14.3 and 12qter. Somat Cell Mol Genet 1991;17:207–214.
Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino KH, Morris CF, McNiece IK, Jacobsen FW, Mendiaz EA, Birkett NC, Smith KA, Johnson MJ, Parker VP, Flores JC, Patel AC, Fisher EF, Erjavec HO, Herrera CJ, Wypych J, Sachdev RK, Pope JA, Leslie I, Wen D, Lin CH, Cupples RL, Zsebo KM: Primary structure and functional expression of rat and human stem cell factor DNAs. Cell 1990;63:203–211.
Mathew S, Murty VV, Hunziker W, Chaganti RS: Subregional mapping of 13 single-copy genes on the long arm of chromosome 12 by fluorescence in situ hybridization. Genomics 1992;14:775–779.
Miettinen M, Lasota J: KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol 2005;13:205–220.
Ronnstrand L: Signal transduction via the stem cell factor receptor/c-Kit. Cell Mol Life Sci 2004;61:2535–2548.
Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U, Sugahara H, Butterfield JH, Ashman LK, Kanayama Y, Matsuzawa Y, Kitamura Y, Kanakura Y: 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 c-kit product. J Clin Invest 1993;92:1736–1744.
Tsujimura T, Furitsu T, Morimoto M, Isozaki K, Nomura S, Matsuzawa Y, Kitamura Y, Kanakura Y: Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation. Blood 1994;83:2619–2626.
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.
Yanagihori H, Oyama N, Nakamura K, Kaneko F: c-kit mutations in patients with childhood-onset mastocytosis and genotype-phenotype correlation. J Mol Diagn 2005;7:252–257.
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.
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.
Longley BJ, Tyrrell L, Lu SZ, Ma YS, Langley K, Ding TG, Duffy T, Jacobs P, Tang LH, Modlin I: Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet 1996;12:312–314.
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. Br J Haematol 1997;96:374–376.
Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD: A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood 2004;103:3222–3225.
Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A, Aldanondo I, Sanchez L, Dominguez M, Botana LM, Sanchez-Jimenez F, Sotlar K, Almeida J, Escribano L, Orfao A: 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. Blood 2006;108:2366–2372.
Kahler C, Didlaukat S, Feller AC, Merz H: Sensitive and reliable detection of Kit point mutation Asp 816 to Val in pathological material. Diagn Pathol 2007;2:37.
Ma Y, Longley BJ, Wang X, Blount JL, Langley K, Caughey GH: Clustering of activating mutations in c-KIT’s juxtamembrane coding region in canine mast cell neoplasms. J Invest Dermatol 1999;112:165–170.
Piao X, Bernstein A: A point mutation in the catalytic domain of c-kit induces growth factor independence, tumorigenicity, and differentiation of mast cells. Blood 1996;87:3117–3123.
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.
Zappulla JP, Dubreuil P, Desbois S, Létard S, Hamouda NB, Daëron M, Delsol G, Arock M, Liblau RS: Mastocytosis in mice expressing human Kit receptor with the activating Asp816Val mutation. J Exp Med 2005;202:1635–1641.
Ferrao PT, Gonda TJ, Ashman LK: Constitutively active mutant D816VKit induces megakaryocyte and mast cell differentiation of early haemopoietic cells from murine foetal liver. Leuk Res 2003;27:547–555.
Taylor ML, Dastych J, Sehgal D, Sundstrom M, Nilsson G, Akin C, Mage RG, Metcalfe DD: The Kit-activating mutation D816V enhances stem cell factor-dependent chemotaxis. Blood 2001;98:1195–1199.
Taylor ML, Sehgal D, Raffeld M, Obiakor H, Akin C, Mage RG, Metcalfe DD: Demonstration that mast cells, T cells, and B cells bearing the activating kit mutation D816V occur in clusters within the marrow of patients with mastocytosis. J Mol Diagn 2004;6:335–342.
Serve H, Yee NS, Stella G, Sepp-Lorenzino L, Tan JC, Besmer P: Differential roles of PI3-kinase and Kit tyrosine 821 in Kit receptor-mediated proliferation, survival and cell adhesion in mast cells. EMBO J 1995;14:473–483.
Timokhina I, Kissel H, Stella G, Besmer P: Kit signaling through PI 3-kinase and Src kinase pathways: an essential role for Rac1 and JNK activation in mast cell proliferation. EMBO J 1998;17:6250–6262.
Jelacic T, Linnekin D: PKC delta plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant. Blood 2005;105:1923–1929.
Tefferi A, Lasho TL, Brockman SR, Elliott MA, Dispenzieri A, Pardanani A: FIP1L1-PDGFRA and c-kit D816V mutation-based clonality studies in systemic mast cell disease associated with eosinophilia. Haematologica 2004;89:871–873.
Tefferi A, Vardiman JW: Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14–22.
Pardanani A, Brockman SR, Paternoster SF, Flynn HC, Ketterling RP, Lasho TL, Ho CL, Li CY, Dewald GW, Tefferi A: FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104:3038–3045.
Lahortiga I, Akin C, Cools J, Wilson TM, Mentens N, Arthur DC, Maric I, Noel P, Kocabas C, Marynen P, Lessin LS, Wlodarska I, Robyn J, Metcalfe DD: Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion. Haematologica 2008;93:49–56.
Kors JW, Van Doormaal JJ, Breukelman H, Van Voorst Vader PC, De Monchy JG: Long-term follow-up of indolent mastocytosis in adults. J Intern Med 1996;239:157–164.
Frieri M, Alling DW, Metcalfe DD: Comparison of the therapeutic efficacy of cromolyn sodium with that of combined chlorpheniramine and cimetidine in systemic mastocytosis. Results of a double-blind clinical trial. Am J Med 1985;78:9–14.
Godt O, Proksch E, Streit V, Christophers E: Short- and long-term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology 1997;195:35–39.
Barton J, Lavker RM, Schechter NM, Lazarus GS: Treatment of urticaria pigmentosa with corticosteroids. Arch Dermatol 1985;121:1516–1523.
Lavker RM, Schechter NM, Guzzo C, Lazarus GS: Aggressive topical corticosteroid therapy: a novel approach to mast-cell-dependent cutaneous disorders. Dermatologica 1987;175:213–216.
Guzzo C, Lavker R, Roberts LJd, Fox K, Schechter N, Lazarus G: Urticaria pigmentosa. Systemic evaluation and successful treatment with topical steroids. Arch Dermatol 1991;127:191–196.
Czarnetzki BM, Rosenbach T, Kolde G, Frosch PJ: Phototherapy of urticaria pigmentosa: clinical response and changes of cutaneous reactivity, histamine and chemotactic leukotrienes. Arch Dermatol Res 1985;277:105–113.
Tefferi A, Li CY, Butterfield JH, Hoagland HC: Treatment of systemic mast-cell disease with cladribine. N Engl J Med 2001;344:307–309.
Simon J, Lortholary O, Caillat-Vigneron N, Raphaël M, Martin A, Brière J, Barète S, Hermine O, Casassus P, Group AFIRMM (Association française pour les initiatives de recherche sur le mastocyte et les mastocytoses): Interest of interferon alpha in systemic mastocytosis. The French experience and review of the literature. Pathol Biol (Paris) 2004;52:294–299.
Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, Van’t Wout JW, Verhoef G, Gerrits WB, van Dobbenburgh OA, Pasmans SG, Fijnheer R: Cladribine therapy for systemic mastocytosis. Blood 2003;102:4270–4276.
Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A: Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine. Leuk Res 2004;28:127–131.
Hauswirth AW, Simonitsch-Klupp I, Uffmann M, Koller E, Sperr WR, Lechner K, Valent P: Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. Leuk Res 2004;28:249–257.
Tanaka A, Konno M, Muto S, Kambe N, Morii E, Nakahata T, Itai A, Matsuda H: A novel NF-kappaB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. Blood 2005;105:2324–2331.
Gabillot-Carre M, Lepelletier Y, Humbert M, de Sepuvelda P, Hamouda NB, Zappulla JP, Liblau R, Ribadeau-Dumas A, Machavoine F, Letard S, Baude C, Hermant A, Yang Y, Vargaftig J, Bodemer C, Morelon E, Lortholary O, Recher C, Laurent G, Dy M, Arock M, Dubreuil P, Hermine O: Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells. Blood 2006;108:1065–1072.
Pan J, Quintas-Cardama A, Kantarjian HM, Akin C, Manshouri T, Lamb P, Cortes JE, Tefferi A, Giles FJ, Verstovsek S: EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. Blood 2007;109:315–322.
Pan J, Quintas-Cardama A, Manshouri T, Cortes J, Kantarjian H, Verstovsek S: Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406. Cancer Sci 2007;98:1223–1225.
Zermati Y, De Sepulveda P, Féger F, Létard S, Kersual J, Castéran N, Gorochov G, Dy M, Ribadeau Dumas A, Dorgham K, Parizot C, Bieche Y, Vidaud M, Lortholary O, Arock M, Hermine O, Dubreuil P: Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms. Oncogene 2003;22:660–664.
Akin C, Brockow K, D’Ambrosio C, Kirshenbaum AS, Ma Y, Longley BJ, Metcalfe DD: Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol 2003;31:686–692.
Nakagomi N, Hirota S: Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation. Lab Invest 2007;87:365–371.
Pardanani A, Elliott M, Reeder T, Li CY, Baxter EJ, Cross NC, Tefferi A: Imatinib for systemic mast-cell disease. Lancet 2003;362:535–536.
Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL: Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer 2006;107:345–351.
Verstovsek S, Akin C, Manshouri T, Quintás-Cardama A, Huynh L, Manley P, Tefferi A, Cortes J, Giles FJ, Kantarjian H: Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit. Leuk Res 2006;30:1365–1370.
von Bubnoff N, Gorantla SH, Kancha RK, Lordick F, Peschel C, Duyster J: The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107. Leukemia 2005;19:1670–1671.
Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, Bokemeyer C, Deininger MW, Druker BJ, Heinrich MC: Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 2006;66:473–481.
Shah NP, Lee FY, Luo R, Jiang Y, Donker M, Akin C: Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood 2006;108:286–291.
Gleixner KV, Mayerhofer M, Sonneck K, Gruze A, Samorapoompichit P, Baumgartner C, Lee FY, Aichberger KJ, Manley PW, Fabbro D, Pickl WF, Sillaber C, Valent P: Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT. Haematologica 2007;92:1451–1459.
Growney JD, Clark JJ, Adelsperger J, Stone R, Fabbro D, Griffin JD, Gilliland DG: Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood 2005;106:721–724.
Gotlib J, Berubé C, Growney JD, Chen CC, George TI, Williams C, Kajiguchi T, Ruan J, Lilleberg SL, Durocher JA, Lichy JH, Wang Y, Cohen PS, Arber DA, Heinrich MC, Neckers L, Galli SJ, Gilliland DG, Coutré SE: Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood 2005;106:2865–2870.
Gleixner KV, Mayerhofer M, Aichberger KJ, Derdak S, Sonneck K, Böhm A, Gruze A, Samorapoompichit P, Manley PW, Fabbro D, Pickl WF, Sillaber C, Valent P: PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood 2006;107:752–759.
Gotlib J, George TI, Corless C, Linder A, Ruddell A, Akin C, DeAngelo DJ, Kepten I, Lanza C, Heinemann H, Yin O, Gallagher N, Graubert T: The kit tyrosine kinase inhibitor midostaurine (PKC412) exhibits a high response rate in aggressive systemic mastocytosis (ASM): interim results of a phase II trial. ASH Annu Meet Abstr 2007;110:3536.
Verstovsek S, Tefferi A, Jorge C, O’Brien S, Garcia-Manero G, Pardanani A, Akin C, Faderl S, Thomas D, Kantarjian H: Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. ASH Annu Meet Abstr 2007;110:3551.
Rondoni M, Paolini S, Colarossi S, Piccaluga PP, Papayannidis C, Palandri F, Laterza C, De Rosa F, Pregno P, Gatto S, Ottaviani E, Saglio G, Cilloni D, Pane F, Triggiani M, Soverini S, Zaccaria A, Baccarani M, Martinelli G: Response to dasatinib in patients with aggressive systemic mastocytosis with D816V kit mutation. ASH Annu Meet Abstr 2007;110:3562.
Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, Metcalfe DD: Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with ‘idiopathic’ anaphylaxis. Blood 2007;110:2331–2333.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.