Experimental Hematology
Volume 38, Issue 9 , Pages 782-791 , September 2010

KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406)

  • Barbara Peter

      Affiliations

    • Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
    • Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria
  • ,
  • Emir Hadzijusufovic

      Affiliations

    • Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
    • Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria
  • ,
  • Katharina Blatt

      Affiliations

    • Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
  • ,
  • Karoline V. Gleixner

      Affiliations

    • Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
  • ,
  • Winfried F. Pickl

      Affiliations

    • Institute of Immunology, Medical University of Vienna, Vienna, Austria
  • ,
  • Tuddow Thaiwong

      Affiliations

    • Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MI, USA
  • ,
  • Vilma Yuzbasiyan-Gurkan

      Affiliations

    • Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MI, USA
  • ,
  • Michael Willmann

      Affiliations

    • Department for Companion Animals and Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna, Austria
  • ,
  • Peter Valent

      Affiliations

    • Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
    • Ludwig Boltzmann Cluster Oncology, Vienna, Austria
    • Corresponding Author InformationOffprint requests to: Peter Valent, M.D., Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090, Austria

Received 27 January 2010 ,Revised 3 May 2010 ,Accepted 17 May 2010.

References 

  1. Valent P, Akin C, Sperr WR, et al. Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol. 2003;122:695–717
  2. Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004;55:419–432
  3. Horny HP, Sotlar K, Valent P. Mastocytosis: state of the art. Pathobiology. 2007;74:121–132
  4. Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112:946–956
  5. Valent P, Horny H-P, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Conference Report of “Year 2000 Working Conference on Mastocytosis.”. Leuk Res. 2001;25:603–625
  6. Valent P, Akin C, Sperr WR, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res. 2003;27:635–641
  7. Valent P, Ghannadan M, Akin C, et al. On the way to targeted therapy of mast cell neoplasms: identification of molecular targets in neoplastic mast cells and evaluation of arising treatment concepts. Eur J Clin Invest. 2004;34:41–52
  8. Pardanani A, Akin C, Valent P. Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Pract Res Clin Haematol. 2006;19:595–615
  9. Gotlib J. KIT mutations in mastocytosis and their potential as therapeutic targets. Immunol Allergy Clin North Am. 2006;26:575–592
  10. 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
  11. Longley BJ, Tyrrell L, Lu SZ, et al. 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
  12. Longley BJ, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-kit catalytic domain mutations in distinct forms of human mastocytosis. Proc Natl Acad Sci U S A. 1999;96:1609–1614
  13. 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
  14. Feger F, Ribadeau Dumas A, Leriche L, Valent P, Arock M. Kit and c-kit mutations in mastocytosis: a short overview with special reference to novel molecular and diagnostic concepts. Int Arch Allergy Immunol. 2002;127:110–114
  15. Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. 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
  16. 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 the c-kit product. J Clin Invest. 1993;92:1736–1744
  17. London CA, Galli SJ, Yuuki T, et al. Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit. Exp Hematol. 1999;27:689–697
  18. Jones CL, Grahn RA, Chien MB, et al. Detection of c-kit mutations in canine mast cell tumors using fluorescent polyacrylamide gel electrophoresis. J Vet Diagn Invest. 2004;16:95–100
  19. Zemke D, Yamini B, Yuzbasiyan-Gurkan V. Mutations in the juxtamembrane domain of c-KIT are associated with higher grade mast cell tumors in dogs. Vet Pathol. 2002;39:529–535
  20. Riva F, Brizzola S, Stefanello D, et al. A study of mutations in the c-kit gene of 32 dogs with mastocytoma. J Vet Diagn Invest. 2005;17:385–388
  21. Gleixner KV, Mayerhofer M, Rix U, et al. Delineation of a KIT-independent oncogenic pathway in neoplastic mast cells that involves Lyn and Btk and can be disrupted by the KIT/Lyn/Btk-targeting drug dasatinib. [abstract] Blood. 2007;110:460;Abstract 1541
  22. Frost MJ, Ferrao PT, Hughes TP, Ashman LK. Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther. 2002;1:1115–1124
  23. Akin C, Brockow K, D'Ambrosio C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated forms of c-kit. Exp Hematol. 2003;31:686–692
  24. 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. Blood. 2002;99:1741–1744
  25. Growney JD, Clark JJ, Adelsperger J, et al. Activation mutations of human c-KIT resistant to imatinib are sensitive to the tyrosine kinase inhibitor PKC412. Blood. 2005;106:721–724
  26. Gotlib J, Berube C, Growney JD, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005;106:2865–2870
  27. Gleixner KV, Mayerhofer M, Aichberger KJ, et al. The tyrosine kinase-targeting drug 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
  28. 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 the majority of patients with systemic mastocytosis. Blood. 2006;108:286–291
  29. Schittenhelm MM, Shiraga S, Schroeder A, et al. 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
  30. Purtill D, Cooney J, Sinniah R, et al. Dasatinib therapy for systemic mastocytosis: four cases. Eur J Haematol. 2008;80:456–458
  31. Verstovsek S, Tefferi A, Cortes J, et al. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Clin Cancer Res. 2008;14:3906–3915
  32. Gotlib J, George TI, Linder A, et al. Phase II trial of the tyrosine kinase inhibitor PKC412 in advanced systemic mastocytosis: preliminary results. Blood. 2006;108:3609
  33. Hantschel O, Rix U, Schmidt U, et al. The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib. Proc Natl Acad Sci U S A. 2007;104:13283–13288
  34. Rix U, Hantschel O, Dürnberger G, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110:4055–4063
  35. Kimura S, Naito H, Segawa H, et al. NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood. 2005;106:3948–3954
  36. Yokota A, Kimura S, Masuda S, et al. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood. 2007;109:306–314
  37. Pan J, Quintás-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
  38. Butterfield JH, Weiler D, Dewald G, Gleich GJ. Establishment of an immature mast cell line from a patient with mast cell leukemia. Leuk Res. 1988;12:345–355
  39. DeVinney R, Gold WM. Establishment of two dog mastocytoma cell lines in continuous culture. Am J Respir Cell Mol Biol. 1990;3:413–420
  40. Rebuzzi L, Willmann M, Sonneck K, et al. Detection of vascular endothelial growth factor (VEGF) and VEGF receptors Flt-1 and KDR in canine mastocytoma cells. Vet Immunol Immunopathol. 2007;115:320–333
  41. Escribano L, Diaz-Agustin B, López A, et al. Immunophenotypic analysis of mast cells in mastocytosis: when and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry B Clin Cytom. 2004;58:1–8
  42. Horny HP, Valent P. Diagnosis of mastocytosis: general histopathological aspects, morphological criteria, and immunohistochemical findings. Leuk Res. 2001;25:543–551
  43. Krauth MT, Födinger M, Rebuzzi L, Greul R, Chott A, Valent P. Aggressive systemic mastocytosis with sarcoma-like growth in the skeleton, leukemic progression, and partial loss of mast cell differentiation antigens. Haematologica. 2007;92:e126–e129
  44. Webster JD, Kiupel M, Yuzbasiyan-Gurkan V. Evaluation of the kinase domain of c-KIT in canine cutaneous mast cell tumors. BMC Cancer. 2006;6:85
  45. Van Cruchten S, Van Den Broeck W. Morphological and biochemical aspects of apoptosis, oncosis and necrosis. Anat Histol Embryol. 2002;31:214–223
  46. Hadzijusufovic E, Rebuzzi L, Gleixner KV, et al. Targeting of heat-shock protein 32/heme oxygenase-1 in canine mastocytoma cells is associated with reduced growth and induction of apoptosis. Exp Hematol. 2008;36:1461–1470
  47. Gleixner KV, Rebuzzi L, Mayerhofer M, et al. Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells. Exp Hematol. 2007;35:1510–1521
  48. Morey AL, Wanigesekera GD, Hawkins NJ, Ward RL. C-kit mutations in gastrointestinal stromal tumours. Pathology. 2002;34:315–319
  49. Nakahara M, Isozaki K, Hirota S, et al. A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors. Gastroenterology. 1998;115:1090–1095
  50. Büttner 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
  51. Bougherara H, Subra F, Crépin R, Tauc P, Auclair C, Poul MA. The aberrant localization of oncogenic kit tyrosine kinase receptor mutants is reversed on specific inhibitory treatment. Mol Cancer Res. 2009;7:1525–1533
  52. Ohmori K, Kawarai S, Yasuda N, et al. Identification of c-kit mutations-independent neoplastic cell proliferation of canine mast cells. Vet Immunol Immunopathol. 2008;126:43–53
  53. Isotani M, Ishida N, Tominaga M, et al. Effect of tyrosine kinase inhibition by imatinib mesylate on mast cell tumors in dogs. J Vet Intern Med. 2008;22:985–988
  54. Maekawa T. Innovation of clinical trials for anti-cancer drugs in Japan—proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia. Gan To Kagaku Ryoho. 2007;34:301–304

PII: S0301-472X(10)00200-6

doi: 10.1016/j.exphem.2010.05.004

Experimental Hematology
Volume 38, Issue 9 , Pages 782-791 , September 2010