• 1
    Valent P, Akin C, Sperr WR, et al. Mastocytosis: pathology, genetics, and current options for therapy. Leuk Lymphoma. 2005; 46: 3548.
  • 2
    Pardanani A. Systemic mastocytosis: bone marrow pathology, classification, and current therapies. Acta Haematol. 2005; 114: 4151.
  • 3
    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: 17361744.
  • 4
    Carrera CJ, Terai C, Lotz M, et al. Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy. J Clin Invest. 1990; 86: 14801488.
  • 5
    Valent P, Horny HP, Li CY, et al. Mastocytosis (mast cell disease). In: JaffeES, HarrisNL, Steinhand VardimanJW, editors. World Health Organization (WHO) Classification of Tumors. Pathology and Genetics. Tumors of Hematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001: 291302.
  • 6
    Valent P, Spanblochl E, Sperr WR, et al. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood. 1992; 80: 22372245.
  • 7
    Sperr WR, Horny HP, Lechner K, Valent P. Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. Leuk Lymphoma. 2000; 37(5–6): 473486.
  • 8
    Sotlar K, Fridrich C, Mall A, et al. Detection of c-kit point mutation Asp-816[RIGHTWARDS ARROW]Val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res. 2002; 26: 979984.
  • 9
    Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003; 101: 46604666.
  • 10
    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: 871873.
  • 11
    Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004; 104: 30383045.
  • 12
    Horny HP, Sotlar K, Sperr WR, Valent P. Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge. J Clin Pathol. 2004; 57: 604608.
  • 13
    Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001; 25: 603625.
  • 14
    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: 635641.
  • 15
    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: 205220.
  • 16
    Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R. Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells. 2005; 23: 1643.
  • 17
    Mol CD, Lim KB, Sridhar V, et al. Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem. 2003; 278: 3146131464.
  • 18
    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 USA. 1995; 92: 1056010564.
  • 19
    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: 357364.
  • 20
    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: 312314.
  • 21
    Akin C, Kirshenbaum AS, Semere T, et al. 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: 140147.
  • 22
    Akin C. Multilineage hematopoietic involvement in systemic mastocytosis. Leuk Res. 2003; 27: 877878.
  • 23
    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: 21202129.
  • 24
    Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003; 102: 30933096.
  • 25
    Swolin B, Rodjer S, Roupe G. Cytogenetic studies in patients with mastocytosis. Cancer Genet Cytogenet. 2000; 120: 131135.
  • 26
    Lishner M, Confino-Cohen R, Mekori YA, et al. Trisomies 9 and 8 detected by fluorescence in situ hybridization in patients with systemic mastocytosis. J Allergy Clin Immunol. 1996; 98: 199204.
  • 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: 880882.
  • 28
    Gotlib J, Cools J, Malone JM3rd, Schrier SL, Gilliland DG, Coutre SE. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood. 2004; 103: 28792891.
  • 29
    Griffin JH, Leung J, Bruner RJ, Caligiuri MA, Briesewitz R. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci USA. 2003; 100: 78307835.
  • 30
    Austen KF. Systemic mastocytosis. N Engl J Med. 1992; 326: 639640.
  • 31
    Worobec AS. Treatment of systemic mast cell disorders. Hematol Oncol Clin North Am. 2000; 14: 659687,vii.
  • 32
    Valent P, Akin C, Sperr WR, et al. Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol. 2003; 122: 695717.
  • 33
    Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004; 55: 419432.
  • 34
    Tefferi A, Pardanani A. Clinical, genetic, and therapeutic insights into systemic mast cell disease. Curr Opin Hematol. 2004; 11: 5864.
  • 35
    Butterfield JH. Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis. Acta Haematol. 2005; 114: 2640.
  • 36
    Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A. Treatment of systemic mast cell disease with 2-chlorodeoxyadenosine. Leuk Res. 2004; 28: 127131.
  • 37
    Akin C, Brockow, K, D'Ambrosio, C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol. 2003; 31: 686692.
  • 38
    Pignon JM, Giraudier S, Duquesnoy P, et al. A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol. 1997; 96: 374376.
  • 39
    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: 307309.
  • 40
    Longley BJJr., 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 USA. 1999; 96: 16091614.
  • 41
    Akin C, Fumo G, Yavuz AS, et al. A novel form of mastocytosis associated with a transmembrane c-Kit mutation and response to imatinib. Blood. 2004; 103: 32223225.
  • 42
    Tang X, Boxer M, Drummond A, Ogston P, Hodgins M, Burden AD. A germline mutation in KIT in familial diffuse cutaneous mastocytosis. J Med Genet. 2004; 41: e88.
  • 43
    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: 12271231.
  • 44
    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. Cancer. 2001; 92: 657662.
  • 45
    Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996; 56: 100104.
  • 46
    Druker B, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996; 2: 561566.
  • 47
    Apperley J, Gardembas M, Melo JV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002; 347: 481487.
  • 48
    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: 139145.
  • 49
    Heinrich M, Griffith DJ, Druker BJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI571, a selective tyrosine kinase inhibitor. Blood. 2000; 96: 925932.
  • 50
    Frost M, Ferrao PT, Hughes TP, et al. 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: 11151124.
  • 51
    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: 17411744.
  • 52
    Pardanani A, Baek JY, Li CY, et al. Systemic mast cell disease without associated hematologic disorder. A combined retrospective and prospective study. Mayo Clin Proc. 2002; 77: 11691175.
  • 53
    Pardanani A, Reeder T, Li CY, et al. Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia. Leuk Res. 2003; 27: 883885.
  • 54
    Cools J, DeAngelo DJ, Gotlib J. et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003; 348: 12011214.
  • 55
    Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast cell disease. Lancet. 2003; 362: 535537.
  • 56
    Droogendijk H, Kluin-Nelemans J, van Daele PLA. Imatinib mesylate in the treatment of systemic mastocytosis, a Phase I/II trial. Blood. 2004; 104: 1516. Abstract
  • 57
    Gleixner K, Mayerhofer M, Aichberger KJ, et al. 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: 752759.
  • 58
    Tefferi A, Pardanani A. Systemic mastocytosis: current concepts and treatment advances. Curr Hematol Rep. 2004; 3: 197202.
  • 59
    Worobec A, Metcalfe DD. Mastocytosis: current treatment concepts. Int Arch Allergy Immunol. 2002; 127: 153155.
  • 60
    Pitini V, Arrigo C, Azzarello D, et al. Serum concentration of cardiac troponin T in patients with hypereosinophilic syndrome treated with imatinib is predictive of adverse outcomes. Blood. 2003; 102: 34563457.
  • 61
    Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005; 7: 129141.
  • 62
    von Bubnoff N, Gorantla SHP, Kancha RK, et al. The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107. Leukemia. 2005; 19: 16701671.
  • 63
    Verstovsek S, Akin C, Giles FJ, et al. Effects of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, on human mast cells bearing wild-type or mutated codon 816 c-kit. Blood. 2005; 106: 3528. Abstract
  • 64
    Lombardo L, Lee FY, Chen P, et al. Discovery of N-(2-chloro- 6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)- 2-methylpyrimidin-4-ylamino)-thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004; 47: 66586661.
  • 65
    Shah N, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004; 305: 399401.
  • 66
    Schittenhelm M, 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: 473481.
  • 67
    Shah N, Lee FY, Luo R, et al. 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: 286291.
  • 68
    Fabbro D, Ruetz S, Bodis S, et al. PKC412-a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000; 15: 1728.
  • 69
    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: 28652870.
  • 70
    Growney J, 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: 721724.
  • 71
    Petti F, Thelemann A, Kahler J, et al. Temporal quantitation of mutant Kit tyrosine kinase signaling attenuated by a novel thiophene kinase inhibitor OSI-930. Mol Cancer Ther. 2005; 4: 11861197.
  • 72
    Garton A, Crew APA, Franklin M, et al. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res. 2006; 66: 10151024.
  • 73
    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: 110114.
  • 74
    Corbin A, Griswold IJ, La Rosee P, et al. Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. Blood. 2004; 104: 37543757.
  • 75
    Kelly L, Yu JC, Boulton CL, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell. 2002; 1: 421432.
  • 76
    Dorsey J, Jove R, Kraker AJ, et al. The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210 Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells. Cancer Res. 2000; 60: 31273131.
  • 77
    Wisniewski D, Lambek CL, Liu C, et al. Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Res. 2002; 62: 42444255.
  • 78
    Corbin A, Demehri S, Griswold IJ, et al. In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit. Blood. 2005; 106: 227234.
  • 79
    Liao A, Chien MB, Shenoy N, et al. Inhibition of constitutively active forms of mutant kit by multitargeted indoli none tyrosine kinase inhibitors. Blood. 2002; 100: 585593.
  • 80
    Gazit A, Yee K, Uecker A, et al. Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. Bioorg Med Chem. 2003; 11: 20072018.
  • 81
    Whitesell L, Shifrin SD, Schwab G, et al. Benzoquinonoid ansamycins possess selective tumoricidal activity unrelated to src kinase inhibition. Cancer Res. 1992; 52: 17211728.
  • 82
    Whitesell L, Mimnaugh EG, De Costa B, et al. Inhibition of heat shock protein HSP90–pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA. 1994; 91: 83248328.
  • 83
    Neckers L. Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med. 2002; 8: S55S61.
  • 84
    Fumo G, Akin C, Metcalfe DD, et al. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells. Blood. 2004; 103: 10781084.
  • 85
    Cohen-Saidon C, Razin E. The involvement of Bcl-2 in mast cell apoptosis. Novartis Found Symp. 2005; 271: 191195; discussion, 195–199.
  • 86
    Cohen-Saidon C, Carmi I, Keren A, Razin E. Antiapoptotic function of Bcl-2 in mast cells is dependent on its association with heat shock protein 90beta. Blood. 2006; 107: 14131420.
  • 87
    Barnes P, Karin M. Nuclear factor-kB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997; 336: 10661071.
  • 88
    Ghosh S, May M, Kopp E. NF-kB and Rel proteins: evolutionarily conserved mediators of immune response. Annu Rev Immunol. 1998; 16: 225260.
  • 89
    Joyce D, Albanese C, Steer J, et al. NF-kB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev. 2001; 12: 7390.
  • 90
    Takebayashi T, Higashi H, Sudo H, et al. NF-kappa B-dependent induction of cyclin D1 by retinoblastoma protein (pRB) family proteins and tumor-derived pRB mutants. J Biol Chem. 2003; 278: 1489714905.
  • 91
    Tanaka A, Konno M, Muto S, et al. A novel NF-kB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. Blood. 2005; 105: 23242331.
  • 92
    Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001; 61: 30713076.
  • 93
    Ning ZQ, Li J, Arceci RJ. Signal transducer and activator of transcription 3 activation is required for Asp(816) mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells. Blood. 2001; 97: 35593567.
  • 94
    Gabillot-Carre M, Lepelletier Y, Humbert M, et al. Rapamycin inhibits growth and survival of D-816-V-mutated c-kit mast cells. Blood. 2006; 108: 10651072.
  • 95
    Sotlar K, Horny HP, Simonitsch I, et al. 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 Pathol. 2004; 28: 13191325.
  • 96
    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( Suppl 2): 4152.
  • 97
    Williams D, Snider CE, Strom TB, et al. Structure/function analysis of interleukin-2-toxin (DAB486IL-2): fragment B sequences required for the delivery of fragment A to the cytosol of target cells. J Biol Chem. 1990; 265: 1188511889.
  • 98
    Kiyokawa T, Williams DP, Snider CE, et al. Protein engineering of diphtheria-toxin-related interleukin-2 fusion toxins to increase cytotoxic potency for high-affinity IL-2-receptor-bearing target cells. Protein Eng. 1991; 4: 463468.
  • 99
    Bacha P, Williams DP, Waters C, et al. Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein. J Exp Med. 1988; 167: 612622.
  • 100
    Foss F. DAB(389)IL-2 (denileukin diftitox, ONTAK): a new fusion protein technology. Clin Lymphoma. 2000; 1( Suppl 21): S27S31.
  • 101
    Olsen E, Duvic M, Frankel A, et al. Pivotal Phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001; 19: 376388.
  • 102
    Giles F, Kantarjian HM, Kornblau SM, et al. Myelotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer. 2001; 92; 406413.
  • 103
    Matthews D, Appelbaum FR, Eary JF, et al. Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood. 1999; 94: 12371247.
  • 104
    Frankel A, Beran, M, Hogge DE, et al. Malignant progenitors from patients with CD87+ acute myelogenous leukemia are sensitive to a diphtheria toxin-urokinase fusion protein. Exp Hematol. 2002; 30: 13161323.