Constitutive Activation of C- kit by the Juxtamembrane but Not the Catalytic Domain Mutations Is Inhibited Selectively by Tyrosine Kinase Inhibitors STI571 and AG1296 Authors
Progress in hematology
Received: 27 June 2002 Accepted: 09 August 2002 DOI:
Cite this article as: Ueda, S., Ikeda, H., Mizuki, M. et al. Int J Hematol (2002) 76: 427. doi:10.1007/BF02982808
The c-kit receptor tyrosine kinase (KIT) is constitutively activated by 2 types of naturally occurring mutations, the Val559→Gly (G559) mutation in the juxtamembrane domain and the Asp814→Val (V814) mutation in the catalytic domain. We evaluated the effects of the tyrosine kinase inhibitors STI571 and AG1296 on BaF3 cells expressing wild-type KIT (KIT
WT) or activating mutants of KIT (KIT G559 and KIT V814) in the presence or absence of the KIT ligand, stem cell factor (SCF). Both STI571 and AG1296 inhibited SCF-dependent activation of KIT WT and SCF-independent activation of KIT G559 more efficiently, whereas SCF-independent activation of KIT V814 was scarcely affected. Furthermore, both inhibitors inhibited SCF-dependent growth of BaF3-KIT WT cells and, with higher potencies, SCF-independent growth of BaF3-KIT G559 cells through the induction of apoptosis. In contrast, the inhibitors had little or no effect on SCF-independent growth of BaF3-KIT V814 cells or on IL-3-dependent growth of BaF3-Mock cells. These results suggested that both inhibitors may be effective therapeutic agents for oncogenic KIT with the juxtamembrane domain mutation, but not with the catalytic domain mutation, and that the activation mechanism of the catalytic domain mutant KIT is complex and entirely different from that of the wild-type KIT or the juxtamembrane domain mutant KIT. Int J Hematol. 2002; 76: 427-435.
Tyrosine kinase inhibitor
Qiu FH, Ray P, Brown K, et al. Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family—oncogenic activation of v-kit involves deletion of extracellular domain and C terminus.
1988; 7: 1003–1011.
Yarden Y, Kuang WJ, Yang-Feng T, et al. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand.
1987; 6: 3341–3351.
Galli SJ, Kitamura Y. Genetically masT-cell-deficient W/Wv and Sl/Sld mice: their value for the analysis of the roles of mast cells in biologic responses in vivo.
Am J Pathol.
1987; 127: 191–198.
Isozaki K, Hirota S, Nakama A, et al. Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit-expressing cells in Ws/Ws mutant rats.
. 1995; 109: 456–464.
Kitamura Y. Heterogeneity of mast cells and phenotypic change between subpopulations.
Annu Rev Immunol
. 1989; 7: 59–76.
Russell ES. Hereditary anemias of the mouse: a review for geneticists.
1979; 20: 357–459.
Ueda S, Mizuki M, Ikeda H, et al. Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration.
. 2002; 99: 3342–3349.
Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.
. 1998; 279: 577–580.
Kitayama H, Kanakura Y, Furitsu T, et al. Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines.
. 1995; 85: 790–798.
Kitayama H, Tsujimura T, Matsumura I, et al. Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase.
. 1996; 88: 995–1004.
Furitsu T, Tsujimura T, Tono T, et al. 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.
Dror Y, Leaker M, Caruana G, Bernstein A, Freedman MH. Mastocytosis cells bearing a c-kit activating point mutation are characterized by hypersensitivity to stem cell factor and increased apoptosis.
Br J Haematol.
2000; 108: 729–736.
Fritsche-Polanz R, Jordan JH, Feix A, et al. Mutation analysis of C-KIT in patients with myelodysplastic syndromes without mastocytosis and cases of systemic mastocytosis.
Br J Haematol.
2001; 113: 357–364.
Longley BJ Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis.
Proc Natl Acad Sci U S A.
1999; 96: 1609–1614.
Nagata H, Worobec AS, Oh CK, et al. 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 U S A.
1995; 92: 10560–10564.
Reinacher-Schick A, Petrasch S, Longley BJ, Teschendorf C, Graeven U, Schmiegel W. c-kit mutation and osteopetrosis-like osteopathy in a patient with systemic mast cell disease.
1998; 77: 131–134.
Sperr WR, Walchshofer S, Horny HP, et al. 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.
Tsujimura T, Furitsu T, Morimoto M, et al. Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocy-toma cell line P-815 generated by a point mutation.
. 1994; 83: 2619–2626.
Tsujimura T, Furitsu T, Morimoto M, et al. Substitution of an aspartic acid results in constitutive activation of c-kit receptor tyrosine kinase in a rat tumor mast cell line RBL-2H3.
Int Arch Allergy Immunol.
1995; 106: 377–385.
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.
. 1998; 83: 2120–2129.
Tsujimura T, Morimoto M, Hashimoto K, et al. Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain.
. 1996; 87: 273–283.
Nakahara M, Isozaki K, Hirota S, et al. A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors.
Gas-troenterology. 1998; 115: 1090–1095.
Nishida T, Nakamura J,Taniguchi M, et al. Clinicopathological features of gastric stromal tumors.
J Exp Clin Cancer Res.
2000; 19: 417–425.
Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors.
2001; 61: 8118–8121.
Taniguchi M, Nishida T, Hirota S, et al. Effect of c-kit mutation on prognosis of gastrointestinal stromal tumors.
1999; 59: 4297–4300.
Nishida T, Hirota S, Taniguchi M, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene.
1998; 19: 323–324.
Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa.
. 2001; 92: 657–662.
Maeyama H, Hidaka E, Ota H, et al. Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene.
. 2001; 120: 210–215.
Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.
1996; 2: 561–566.
Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
N Engl J Med.
2001; 344: 1038–1042.
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
N Engl J Med.
2001; 344: 1031–1037.
Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors.
J Pharmacol Exp Ther.
2000; 295: 139–145.
Kovalenko M, Gazit A, Bohmer A, et al. Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation.
1994; 54: 6106–6114.
Mizushima S, Nagata S. pEF-BOS, a powerful mammalian expression vector.
Nucleic Acids Res.
1990; 18: 5322.
Ma Y, Zeng S, Metcalfe DD, et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors: kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations.
. 2002; 99: 1741–1744.
Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor.
N Engl J Med.
2001; 344: 1052–1056.
van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study.
. 2001; 358: 1421–1423.
Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications.
. 2001; 20: 5054–5058.
Tsujimura T, Hashimoto K, Kitayama H, et al. Activating mutation in the catalytic domain of c-kit elicits hematopoietic transformation by receptor self-association not at the ligand-induced dimerization site.
. 1999; 93: 1319–1329.
Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.
. 2001; 293: 876–880.
Weisberg E, Griffin JD. Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hemato-poietic cell lines.
. 2000; 95: 3498–3505.
von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study.
. 2002; 359: 487–491.
Kovalenko M, Ronnstrand L, Heldin CH, et al. Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296.
. 1997; 36: 6260–6269.
PubMed CrossRef Copyright information
© The Japanese Society of Hematology 2002