Receptor Tyrosine Kinase Alterations in AML – Biology and Therapy

  • Derek L. Stirewalt
  • Soheil Meshinchi
Part of the Cancer Treatment and Research book series (CTAR, volume 145)


Acute myeloid leukemia (AML) is the most common form of leukemia in adults, and despite some recent progress in understanding the biology of the disease, AML remains the leading cause of leukemia-related deaths in adults and children. AML is a complex and heterogeneous disease, often involving multiple genetic defects that promote leukemic transformation and drug resistance. The cooperativity model suggests that an initial genetic event leads to maturational arrest in a myeloid progenitor cell, and subsequent genetic events induce proliferation and block apoptosis. Together, these genetic abnormalities lead to clonal expansion and frank leukemia. The purpose of this chapter is to review the biology of receptor tyrosine kinases (RTKs) in AML, exploring how RTKs are being used as novel prognostic factors and potential therapeutic targets.


Acute Myeloid Leukemia Small Molecule Inhibitor Acute Myeloid Leukemia Patient Acute Myeloid Leukemia Cell Internal Tandem Duplication 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Support for the authors was provided by National Institutes of Health grants (K23 CA92405 and CA 114563). This work was supported by National Institute of Health grants no. K23 CA92405-01 and CA18029.


  1. 1.
    Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol. 2001;113:983–988.PubMedCrossRefGoogle Scholar
  2. 2.
    Abu-Duhier FM, Goodeve AC, Wilson GA, et al. FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol. 2000;111:190–195.PubMedCrossRefGoogle Scholar
  3. 3.
    Agnes F, Shamoon B, Dina C, Rosnet O, Birnbaum D, Galibert F. Genomic structure of the downstream part of the human FLT3 gene: exon/intron structure conservation among genes encoding receptor tyrosine kinases (RTK) of subclass III. Gene. 1994;145:283–288.PubMedCrossRefGoogle Scholar
  4. 4.
    Aguayo A, Estey E, Kantarjian H, et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood. 1999;94:3717–3721.PubMedGoogle Scholar
  5. 5.
    Anstrom KJ, Reed SD, Allen AS, Glendenning GA, Schulman KA. Long-term survival estimates for imatinib versus interferon-alpha plus low-dose cytarabine for patients with newly diagnosed chronic-phase chronic myeloid leukemia. Cancer. 2004;101:2584–2592.PubMedCrossRefGoogle Scholar
  6. 6.
    Armstrong SA, Kung AL, Mabon ME, et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 2003;3:173–183.PubMedCrossRefGoogle Scholar
  7. 7.
    Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002;30:41–47.PubMedCrossRefGoogle Scholar
  8. 8.
    Beghini A, Larizza L, Cairoli R, Morra E. c-kit activating mutations and mast cell proliferation in human leukemia. Blood. 1998;92:701–702.PubMedGoogle Scholar
  9. 9.
    Beghini A, Peterlongo P, Ripamonti CB, et al. C-kit mutations in core binding factor leukemias. Blood. 2000;95:726–727.PubMedGoogle Scholar
  10. 10.
    Beghini A, Ripamonti CB, Cairoli R, et al. KIT activating mutations: incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication. Haematologica. 2004;89:920–925.PubMedGoogle Scholar
  11. 11.
    Beghini A, Ripamonti CB, Castorina P, et al. Trisomy 4 leading to duplication of a mutated KIT allele in acute myeloid leukemia with mast cell involvement. Cancer Genet Cytogenet. 2000;119:26–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Bentires-Alj M, Paez JG, David FS, et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 2004;64:8816–8820.PubMedCrossRefGoogle Scholar
  13. 13.
    Birkenkamp KU, Geugien M, Lemmink HH, Kruijer W, Vellenga E. Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts. Leukemia. 2001;15:1923–1931.PubMedGoogle Scholar
  14. 14.
    Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355–365.PubMedCrossRefGoogle Scholar
  15. 15.
    Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–4689.PubMedGoogle Scholar
  16. 16.
    Boultwood J, Rack K, Kelly S, et al. Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion. Proc Natl Acad Sci USA. 1991;88:6176–6180.PubMedCrossRefGoogle Scholar
  17. 17.
    Bowen DT, Frew ME, Hills R, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood. 2005;106:2113–2119.PubMedCrossRefGoogle Scholar
  18. 18.
    Brandts CH, Sargin B, Rode M, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005;65:9643–9650.PubMedCrossRefGoogle Scholar
  19. 19.
    Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias. An Italian retrospective study. Blood. 2006. In press.Google Scholar
  20. 20.
    Cairoli R, Beghini A, Morello E, et al. Imatinib mesylate in the treatment of Core Binding Factor leukemias with KIT mutations. A report of three cases. Leuk Res. 2005;29:397–400.PubMedCrossRefGoogle Scholar
  21. 21.
    Cairoli R, Grillo G, Beghini A, et al. C-Kit point mutations in core binding factor leukemias: correlation with white blood cell count and the white blood cell index. Leukemia. 2003;17:471–472.PubMedCrossRefGoogle Scholar
  22. 22.
    Callens C, Chevret S, Cayuela JM, et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia. 2005;19:1153–1160.PubMedCrossRefGoogle Scholar
  23. 23.
    Cammenga J, Horn S, Bergholz U, et al. Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate. Blood. 2005;106:3958–3961.PubMedCrossRefGoogle Scholar
  24. 24.
    Care RS, Valk PJ, Goodeve AC, et al. Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol. 2003;121:775–777.PubMedCrossRefGoogle Scholar
  25. 25.
    Carroll M, Tomasson MH, Barker GF, Golub TR, Gilliland DG. The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways. Proc Natl Acad Sci USA. 1996;93:14845–14850.PubMedCrossRefGoogle Scholar
  26. 26.
    Casey G, Rudzki Z, Roberts M, Hutchins C, Juttner C. N-ras mutation in acute myeloid leukemia: incidence, prognostic significance and value as a marker of minimal residual disease. Pathology. 1993;25:57–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Christiansen DH, Andersen MK, Desta F, Pedersen-Bjergaard J. Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2005;19:2232–2240.PubMedCrossRefGoogle Scholar
  28. 28.
    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;348:1201–1214.PubMedCrossRefGoogle Scholar
  29. 29.
    Cools J, Stover EH, Gilliland DG. Detection of the FIP1L1-PDGFRA fusion in idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia. Methods Mol Med. 2006;125:177–187.PubMedGoogle Scholar
  30. 30.
    Cools J, Stover EH, Wlodarska I, Marynen P, Gilliland DG. The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia. Curr Opin Hematol. 2004;11:51–57.PubMedCrossRefGoogle Scholar
  31. 31.
    De Angelo DJ, Stone RM, Heaney ML, et al. Phase II evaluation of the tyrosine kinase inhibitor MLN518 in patients with acute myeloid leukemia (AML) bearing a FLT3 internal tandem duplication (ITD) mutation. Blood. 2004;104:1792a.Google Scholar
  32. 32.
    Dello Sbarba P, Pollard JW, Stanley ER. Alterations in CSF-1 receptor expression and protein tyrosine phosphorylation in autonomous mutants of a CSF-1 dependent macrophage cell line. Growth Factors. 1991;5:75–85.PubMedCrossRefGoogle Scholar
  33. 33.
    Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000;105:3–7.PubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ. Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc Natl Acad Sci USA. 1988;85:1629–1633.PubMedCrossRefGoogle Scholar
  36. 36.
    Felgner J, Kreipe H, Heidorn K, et al. Increased methylation of the c-fms protooncogene in acute myelomonocytic leukemias. Pathobiology. 1991;59:293–298.PubMedCrossRefGoogle Scholar
  37. 37.
    Fenski R, Flesch K, Serve S, et al. Constitutive activation of FLT3 in acute myeloid leukaemia and its consequences for growth of 32D cells. Br J Haematol. 2000;108:322–330.PubMedCrossRefGoogle Scholar
  38. 38.
    Foran J, O'Farrell AM, Fiedler W, et al. An innovative single dose clinical study shows potent inhibition of FLT3 phosphorylation by SU11248 in vivo: a clinical and pharmacodynamic study in AML patients. Blood. 2002;100:2196a.Google Scholar
  39. 39.
    Foran J, Paquette R, Cooper M, et al. A phase I study of repeated oral dosing with SU11248 for the treatment of patients with acute myeloid leukemia who have failed, or are not eligible for conventional chemotherapy. Blood. 2002;100:2195a.Google Scholar
  40. 40.
    Forrester K, Almoguera C, Han K, Grizzle WE, Perucho M. Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature. 1987;327:298–303.PubMedCrossRefGoogle Scholar
  41. 41.
    Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100:4372–4380.PubMedCrossRefGoogle Scholar
  42. 42.
    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.PubMedCrossRefGoogle Scholar
  43. 43.
    Furuta T, Sakai T, Senga T, et al. Identification of potent and selective inhibitors of PDGF receptor autophosphorylation. J Med Chem. 2006;49:2186–2192.PubMedCrossRefGoogle Scholar
  44. 44.
    Gabbianelli M, Pelosi E, Montesoro E, et al. Multi-level effects of flt3 ligand on human hematopoiesis: expansion of putative stem cells and proliferation of granulomonocytic progenitors/monocytic precursors. Blood. 1995;86:1661–1670.PubMedGoogle Scholar
  45. 45.
    Gari M, Goodeve A, Wilson G, et al. c-kit proto-oncogene exon 8 in-frame deletion plus insertion mutations in acute myeloid leukaemia. Br J Haematol. 1999;105:894–900.PubMedCrossRefGoogle Scholar
  46. 46.
    Giles F, Schiffer C, Kantarjian H, et al. Phase 1 study of PKC412, an oral FLT3 kinase inhibitor, in sequential and concomitant combinations with daunorubicin and cytarabine (DA) induction and high-dose cytarabine consolidation in newly diagnosed patients with AML. Blood. 2004;104:262a.Google Scholar
  47. 47.
    Giles FJ, Stopeck AT, Silverman LR, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood. 2003;102:795–801.PubMedCrossRefGoogle Scholar
  48. 48.
    Gille H, Kowalski J, Yu L, et al. A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3′-kinase activation and endothelial cell migration. Embo J. 2000;19:4064–4073.PubMedCrossRefGoogle Scholar
  49. 49.
    Goemans BF, Zwaan CM, Miller M, et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia. 2005;19:1536–1542.PubMedCrossRefGoogle Scholar
  50. 50.
    Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994;77:307–316.PubMedCrossRefGoogle Scholar
  51. 51.
    Gotlib J, Cools J, Malone JM, 3rd, 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;103:2879–2891.PubMedCrossRefGoogle Scholar
  52. 52.
    Griffith J, Black J, Faerman C, et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell. 2004;13:169–178.PubMedCrossRefGoogle Scholar
  53. 53.
    Grundler R, Miething C, Thiede C, Peschel C, Duyster J. FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood. 2005;105:4792–4799.PubMedCrossRefGoogle Scholar
  54. 54.
    Hayakawa F, Towatari M, Kiyoi H, et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene. 2000;19:624–631.PubMedCrossRefGoogle Scholar
  55. 55.
    Heinrich MC, Druker BJ, Curtin PT, et al. A “first in man” study of the safety and PK/PD of an oral FLT3 inhibitor (MLN518) in patients with AML or high risk myelodyspsia. Blood. 2002;100:1305a.Google Scholar
  56. 56.
    Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–932.PubMedGoogle Scholar
  57. 57.
    Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–2196.PubMedCrossRefGoogle Scholar
  58. 58.
    Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423–1432.PubMedCrossRefGoogle Scholar
  59. 59.
    Iwai T, Yokota S, Nakao M, et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia. 1999;13:38–43.PubMedCrossRefGoogle Scholar
  60. 60.
    Janssen JW, Steenvoorden AC, Lyons J, et al. RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes. Proc Natl Acad Sci USA. 1987;84:9228–9232.PubMedCrossRefGoogle Scholar
  61. 61.
    Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood. 2001;97:3361–3369.PubMedCrossRefGoogle Scholar
  62. 62.
    Karp JE, Lancet JE. Development of the farnesyltransferase inhibitor tipifarnib for therapy of hematologic malignancies. Fut Oncol. 2005;1:719–731.CrossRefGoogle Scholar
  63. 63.
    Karp JE, Lancet JE. Targeting the process of farnesylation for therapy of hematologic malignancies. Curr Mol Med. 2005;5:643–652.PubMedCrossRefGoogle Scholar
  64. 64.
    Kelly LM, Kutok JL, Williams IR, et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci USA. 2002;99:8283–8288.PubMedCrossRefGoogle Scholar
  65. 65.
    Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood. 2002;99:310–318.PubMedCrossRefGoogle Scholar
  66. 66.
    Kelly LM, Yu J, Boulton CL, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Caner Cell. 2002.Google Scholar
  67. 67.
    Kindler T, Breitenbuecher F, Kasper S, et al. Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML). Blood. 2005;105:335–340.PubMedCrossRefGoogle Scholar
  68. 68.
    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. Blood. 1995;85:790–798.PubMedGoogle Scholar
  69. 69.
    Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999;93:3074–3080.PubMedGoogle Scholar
  70. 70.
    Kiyoi H, Ohno R, Ueda R, Saito H, Naoe T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene. 2002;21:2555–2563.PubMedCrossRefGoogle Scholar
  71. 71.
    Kiyoi H, Towatari M, Yokota S, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12:1333–1337.PubMedCrossRefGoogle Scholar
  72. 72.
    Kohl TM, Schnittger S, Ellwart JW, Hiddemann W, Spiekermann K. KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood. 2005;105:3319–3321.PubMedCrossRefGoogle Scholar
  73. 73.
    Kondo M, Horibe K, Takahashi Y, et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol. 1999;33:525–529.PubMedCrossRefGoogle Scholar
  74. 74.
    Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98:1752–1759.PubMedCrossRefGoogle Scholar
  75. 75.
    Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100:2393–2398.PubMedCrossRefGoogle Scholar
  76. 76.
    Kubo K, Naoe T, Kiyoi H, et al. Clonal analysis of multiple point mutations in the N-ras gene in patients with acute myeloid leukemia. Jpn J Cancer Res. 1993;84:379–387.PubMedGoogle Scholar
  77. 77.
    Kuchenbauer F, Feuring-Buske M, Buske C. AML1-ETO needs a partner: new insights into the pathogenesis of t(8;21) leukemia. Cell Cycle. 2005;4:1716–1718.PubMedCrossRefGoogle Scholar
  78. 78.
    Lacayo NJ, Meshinchi S, Kinnunen P, et al. Gene Expression Profiles at Diagnosis in de novo Childhood AML Patients Identify FLT3 Mutations with Good Clinical Outcomes. Blood. 2004.Google Scholar
  79. 79.
    Lancet JE, Karp JE. Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy. Blood. 2003;102:3880–3889.PubMedCrossRefGoogle Scholar
  80. 80.
    Levis M, Allebach J, Fai-Tse K, et al. FLT3-targeted inhibitors kill FLT3-dependent modeled cells, leukemia-derived cell lines, and primary AML blasts in vitro and in vivo. Blood. 2001;89:721a.Google Scholar
  81. 81.
    Levis M, Allebach J, Tse KF, et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002;99:3885–3891.PubMedCrossRefGoogle Scholar
  82. 82.
    Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important in order to achieve synergistic cytotoxic effects. Blood. 2004;104:1145–1150.PubMedCrossRefGoogle Scholar
  83. 83.
    Levis M, Tse KF, Smith BD, Garrett E, Small D. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood. 2001;98:885–887.PubMedCrossRefGoogle Scholar
  84. 84.
    Liang DC, Shih LY, Fu JF, et al. K-Ras mutations and N-Ras mutations in childhood acute leukemias with or without mixed-lineage leukemia gene rearrangements. Cancer. 2006;106:950–956.PubMedCrossRefGoogle Scholar
  85. 85.
    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 USA. 1999;96:1609–1614.PubMedCrossRefGoogle Scholar
  86. 86.
    McCoy MS, Toole JJ, Cunningham JM, Chang EH, Lowy DR, Weinberg RA. Characterization of a human colon/lung carcinoma oncogene. Nature. 1983;302:79–81.PubMedCrossRefGoogle Scholar
  87. 87.
    Mead A, Linch D, Hills R, Wheatley K, Burnett A, Gale R. Favourable prognosis associated with FLT3 tyrosine kinase domain mutations in AML in contrast to the adverse outcome associated with internal tandem duplications. Blood. 2005;106:334a.Google Scholar
  88. 88.
    Meshinchi S, Alonzo TA, Gerbing R, Lang B, Radich J. FLT3 internal tandem duplication (FLT3/ITD) is a prognostic factor for poor outcome in pediatric AML: a CCG2961 study. Blood. 2003;102:335a.CrossRefGoogle Scholar
  89. 89.
    Meshinchi S, Stirewalt DL, Alonzo TA, et al. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood. 2003;102:1474–1479.PubMedCrossRefGoogle Scholar
  90. 90.
    Meshinchi S, Woods WG, Stirewalt DL, et al. Prevalence and prognostic significance of FLT3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97:89–94.PubMedCrossRefGoogle Scholar
  91. 91.
    Mesters RM, Padro T, Bieker R, et al. Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood. 2001;98:241–243.PubMedCrossRefGoogle Scholar
  92. 92.
    Minami Y, Kiyoi H, Yamamoto Y, et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia. 2002;16:1535–1540.PubMedCrossRefGoogle Scholar
  93. 93.
    Minami Y, Yamamoto K, Kiyoi H, Ueda R, Saito H, Naoe T. Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia. Blood. 2003;102:2969–2975.PubMedCrossRefGoogle Scholar
  94. 94.
    Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood. 2000;96:3907–3914.PubMedGoogle Scholar
  95. 95.
    Mizuki M, Schwable J, Steur C, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood. 2003;101:3164–3173.PubMedCrossRefGoogle Scholar
  96. 96.
    Mizuki M, Schwaeble J, Steur C, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood. 2003;101(8):3164–3173.Google Scholar
  97. 97.
    Moore TA, Zlotnik A. Differential effects of Flk-2/Flt-3 ligand and stem cell factor on murine thymic progenitor cells. J Immunol. 1997;158:4187–4192.PubMedGoogle Scholar
  98. 98.
    Morgan MA, Dolp O, Reuter CW. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Blood. 2001;97:1823–1834.PubMedCrossRefGoogle Scholar
  99. 99.
    Murray LJ, Young JC, Osborne LJ, Luens KM, Scollay R, Hill BL. Thrombopoietin, flt3, and kit ligands together suppress apoptosis of human mobilized CD34+ cells and recruit primitive CD34+ Thy-1+ cells into rapid division. Exp Hematol. 1999;27:1019–1028.PubMedCrossRefGoogle Scholar
  100. 100.
    Nakagawa T, Saitoh S, Imoto S, et al. Multiple point mutation of N-ras and K-ras oncogenes in myelodysplastic syndrome and acute myelogenous leukemia. Oncology. 1992;49:114–122.PubMedCrossRefGoogle Scholar
  101. 101.
    Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918.PubMedGoogle Scholar
  102. 102.
    Namikawa R, Muench MO, de Vries JE, Roncarolo MG. The FLK2/FLT3 ligand synergizes with interleukin-7 in promoting stromal-cell-independent expansion and differentiation of human fetal pro-B cells in vitro. Blood. 1996;87:1881–1890.PubMedGoogle Scholar
  103. 103.
    Nanri T, Matsuno N, Kawakita T, et al. Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22). Leukemia. 2005;19:1361–1366.PubMedCrossRefGoogle Scholar
  104. 104.
    Neubauer A, Dodge RK, George SL, et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood. 1994;83:1603–1611.PubMedGoogle Scholar
  105. 105.
    O'Farrell AM, Abrams TJ, Yuen HA, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–3605.PubMedCrossRefGoogle Scholar
  106. 106.
    O'Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500–4505.PubMedCrossRefGoogle Scholar
  107. 107.
    Oliff A. Farnesyltransferase inhibitors: targeting the molecular basis of cancer. Biochimica et Biophysica Acta. 1999;1423:C19–30.Google Scholar
  108. 108.
    Ouyang B, Knauf JA, Smith EP, et al. Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res. 2006;12:1785–1793.PubMedCrossRefGoogle Scholar
  109. 109.
    Padua RA, Guinn BA, Al-Sabah AI, et al. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia. 1998;12:887–892.PubMedCrossRefGoogle Scholar
  110. 110.
    Panka DJ, Wang W, Atkins MB, Mier JW. The Raf inhibitor BAY 43-9006 (Sorafenib) induces caspase-independent apoptosis in melanoma cells. Cancer Res. 2006;66:1611–1619.PubMedCrossRefGoogle Scholar
  111. 111.
    Pellegata NS, Sessa F, Renault B, et al. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res. 1994;54:1556–1560.PubMedGoogle Scholar
  112. 112.
    Prendergast GC, Davide JP, deSolms SJ, et al. Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol Cell Biol. 1994;14:4193–4202.PubMedGoogle Scholar
  113. 113.
    Radich JP, Kopecky KJ, Willman CL, et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood. 1990;76:801–807.Google Scholar
  114. 114.
    Rahmani M, Davis EM, Bauer C, Dent P, Grant S. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005;280:35217–35227.PubMedCrossRefGoogle Scholar
  115. 115.
    Ray RJ, Paige CJ, Furlonger C, Lyman SD, Rottapel R. Flt3 ligand supports the differentiation of early B cell progenitors in the presence of interleukin-11 and interleukin-7. Eur J Immunol. 1996;26:1504–1510.PubMedCrossRefGoogle Scholar
  116. 116.
    Reindl C, Bagrintseva K, Vempati S, et al. Point mutations found in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML. Blood. 2006.Google Scholar
  117. 117.
    Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA. FMS mutations in myelodysplastic, leukemic, and normal subjects. Proc Natl Acad Sci USA. 1990;87:1377–1380.PubMedCrossRefGoogle Scholar
  118. 118.
    Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA. FMS mutations in myelodysplastic, leukemic, and normal subjects. Proc Natl Acad Sci USA. 1990;87:1377–1380.PubMedCrossRefGoogle Scholar
  119. 119.
    Ritter M, Kim TD, Lisske P, Thiede C, Schaich M, Neubauer A. Prognostic significance of N-RAS and K-RAS mutations in 232 patients with acute myeloid leukemia. Haematologica. 2004;89:1397–1399.PubMedGoogle Scholar
  120. 120.
    Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19:5548–5557.PubMedCrossRefGoogle Scholar
  121. 121.
    Rodenhuis S, van de Wetering ML, Mooi WJ, Evers SG, van Zandwijk N, Bos JL. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung. N Engl J Med. 1987;317:929–935.PubMedCrossRefGoogle Scholar
  122. 122.
    Rosenbauer F, Wagner K, Kutok JL, et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet. 2004;36:624–630.PubMedCrossRefGoogle Scholar
  123. 123.
    Roskoski R, Jr. Structure and regulation of Kit protein-tyrosine kinase–the stem cell factor receptor. Biochem Biophys Res Commun. 2005;338:1307–1315.PubMedCrossRefGoogle Scholar
  124. 124.
    Rosnet O, Birnbaum D. Hematopoietic receptors of class III receptor-type tyrosine kinases. Crit Rev Oncog. 1993;4:595–613.PubMedGoogle Scholar
  125. 125.
    Roussel MF, Downing JR, Rettenmier CW, Sherr CJ. A point mutation in the extracellular domain of the human CSF-1 receptor (c-fms proto-oncogene product) activates its transforming potential. Cell. 1988;55:979–988.PubMedCrossRefGoogle Scholar
  126. 126.
    Rusten LS, Lyman SD, Veiby OP, Jacobsen SE. The FLT3 ligand is a direct and potent stimulator of the growth of primitive and committed human CD34+ bone marrow progenitor cells in vitro. Blood. 1996;87:1317–1325.PubMedGoogle Scholar
  127. 127.
    Schessl C, Rawat VP, Cusan M, et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest. 2005;115:2159–2168.PubMedCrossRefGoogle Scholar
  128. 128.
    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.PubMedCrossRefGoogle Scholar
  129. 129.
    Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107:1791–1799.PubMedCrossRefGoogle Scholar
  130. 130.
    Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood. 2002;100:59–66.PubMedCrossRefGoogle Scholar
  131. 131.
    Sebti SM, Der CJ. Opinion: searching for the elusive targets of farnesyltransferase inhibitors. Nat Rev Cancer. 2003;3:945–951.PubMedCrossRefGoogle Scholar
  132. 132.
    SEER Cancer Statistics Review 1975-2001, Vol. 2004. National Cancer Institute; 2004. Accessed on 15 July, 2009.
  133. 133.
    Shah AJ, Smogorzewska EM, Hannum C, Crooks GM. Flt3 ligand induces proliferation of quiescent human bone marrow CD34+CD38− cells and maintains progenitor cells in vitro. Blood. 1996;87:3563–3570.PubMedGoogle Scholar
  134. 134.
    Shimada A, Taki T, Tabuchi K, et al. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood. 2006;107:1806–1809.PubMedCrossRefGoogle Scholar
  135. 135.
    Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990;323:561–565.PubMedCrossRefGoogle Scholar
  136. 136.
    Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669–3676.PubMedCrossRefGoogle Scholar
  137. 137.
    Smith BD, Levis M, Brown P, et al. Single agent CEP-701, a novel FLT-3 inhibitor, shows initial response in patients with refractory acute myeloid leukemia. Blood. 2002;100:314a.CrossRefGoogle Scholar
  138. 138.
    Smith ML, Snadden J, Neat M, et al. Mutation of BRAF is uncommon in AML FAB type M1 and M2. Leukemia. 2003;17:274–275.Google Scholar
  139. 139.
    Smolich BD, Yuen HA, West KA, Giles FJ, Albitar M, Cherrington JM. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood. 2001;97:1413–1421.PubMedCrossRefGoogle Scholar
  140. 140.
    Spiekermann K, Bagrintseva K, Schoch C, Haferlach T, Hiddemann W, Schnittger S. A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood. 2002;100:3423–3425.PubMedCrossRefGoogle Scholar
  141. 141.
    Springall F, O'Mara S, Shounan Y, Todd A, Ford D, Iland H. c-fms point mutations in acute myeloid leukemia: fact or fiction? Leukemia. 1993;7:978–985.PubMedGoogle Scholar
  142. 142.
    Sridhar SS, Hedley D, Siu LL. Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther. 2005;4:677–685.PubMedCrossRefGoogle Scholar
  143. 143.
    Stephenson SA, Slomka S, Douglas EL, Hewett PJ, Hardingham JE. Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC Mol Biol. 2001;2:15.PubMedCrossRefGoogle Scholar
  144. 144.
    Stirewalt DL, Kopecky KJ, Meshinchi S, et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001;97:3589–3595.PubMedCrossRefGoogle Scholar
  145. 145.
    Stirewalt DL, Kopecky KJ, Meshinchi S, et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood. 2006;107:3724–3726.PubMedCrossRefGoogle Scholar
  146. 146.
    Stirewalt DL, Meshinchi S, Kussick SJ, et al. Novel FLT3 point mutations within exon 14 found in patients with acute myeloid leukaemia. Br J Haematol. 2004;124:481–484.PubMedCrossRefGoogle Scholar
  147. 147.
    Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–665.PubMedCrossRefGoogle Scholar
  148. 148.
    Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54–60.PubMedCrossRefGoogle Scholar
  149. 149.
    Stone RM, Fischer T, Paquette R, et al. Phase 1B study of PKC412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine (DA) induction and high-dose consolidation in newly diagnosed patients with AML. Blood. 2005;106:404a.Google Scholar
  150. 150.
    Stone RM, Klimek V, J. DD, et al. PKC412, an oral FLT3 inhibitor, has activity in mutant FLT3 acute myeloid leukemia (AML): a phase II clinical trial. Blood. 2002;100:316a.Google Scholar
  151. 151.
    Tartaglia M, Martinelli S, Iavarone I, et al. Somatic PTPN11 mutations in childhood acute myeloid leukaemia. Br J Haematol. 2005;129:333–339.PubMedCrossRefGoogle Scholar
  152. 152.
    Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335.PubMedCrossRefGoogle Scholar
  153. 153.
    Tobal K, Pagliuca A, Bhatt B, Bailey N, Layton DM, Mufti GJ. Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia. Leukemia. 1990;4:486–489.PubMedGoogle Scholar
  154. 154.
    Tomasson MH, Sternberg DW, Williams IR, et al. Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581. J Clin Invest. 2000;105:423–432.PubMedCrossRefGoogle Scholar
  155. 155.
    Tomasson MH, Williams IR, Hasserjian R, et al. TEL/PDGFbetaR induces hematologic malignancies in mice that respond to a specific tyrosine kinase inhibitor. Blood. 1999;93:1707–1714.PubMedGoogle Scholar
  156. 156.
    Tong FK, Chow S, Hedley D. Pharmacodynamic monitoring of BAY 43-9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells. Cytometry B Clin Cytom. 2006;70(3):107–114.Google Scholar
  157. 157.
    Towatari M, Iida H, Tanimoto M, Iwata H, Hamaguchi M, Saito H. Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia. 1997;11:479–484.PubMedCrossRefGoogle Scholar
  158. 158.
    Tse KF, Allebach J, Levis M, Smith BD, Bohmer FD, Small D. Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia. 2002;16:2027–2036.PubMedCrossRefGoogle Scholar
  159. 159.
    Tse KF, Mukherjee G, Small D. Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia. 2000;14:1766–1776.PubMedCrossRefGoogle Scholar
  160. 160.
    Tsujimura T, Furitsu T, Morimoto M, et al. 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.PubMedGoogle Scholar
  161. 161.
    Tsujimura T, Kanakura Y, Kitamura Y. Mechanisms of constitutive activation of c-kit receptor tyrosine kinase. Leukemia. 1997;11 Suppl 3:396–398.PubMedGoogle Scholar
  162. 162.
    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. Blood. 1996;87:273–283.PubMedGoogle Scholar
  163. 163.
    Turner AM, Lin NL, Issarachai S, Lyman SD, Broudy VC. FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells. Blood. 1996;88:3383–3390.PubMedGoogle Scholar
  164. 164.
    Ueda S, Ikeda H, Mizuki M, et al. Constitutive activation of c-kit by the juxtamembrane but not the catalytic domain mutations is inhibited selectively by tyrosine kinase inhibitors STI571 and AG1296. Int J Hematol. 2002;76:427–435.PubMedCrossRefGoogle Scholar
  165. 165.
    van der Geer P, Hunter T. Identification of tyrosine 706 in the kinase insert as the major colony-stimulating factor 1 (CSF-1)-stimulated autophosphorylation site in the CSF-1 receptor in a murine macrophage cell line. Mol Cell Biol. 1990;10:2991–3002.PubMedGoogle Scholar
  166. 166.
    Vandenberghe P, Wlodarska I, Michaux L, et al. Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia. 2004;18:734–742.PubMedCrossRefGoogle Scholar
  167. 167.
    Veiby OP, Lyman SD, Jacobsen SE. Combined signaling through interleukin-7 receptors and flt3 but not c-kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells. Blood. 1996;88:1256–1265.PubMedGoogle Scholar
  168. 168.
    Vogelstein B, Civin CI, Preisinger AC, et al. RAS gene mutations in childhood acute myeloid leukemia: a Pediatric Oncology Group study. Genes Chromosomes Cancer. 1990;2:159–162.PubMedCrossRefGoogle Scholar
  169. 169.
    Wallace EM, Lyssikatos J, Blake JF, et al. Potent and selective mitogen-activated protein kinase kinase (MEK) 1,2 inhibitors. 1. 4-(4-bromo-2-fluorophenylamino)-1-methylpyridin-2(1H)-ones. J Med Chem. 2006;49:441–444.PubMedCrossRefGoogle Scholar
  170. 170.
    Wang YY, Zhou GB, Yin T, et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA. 2005;102:1104–1109.PubMedCrossRefGoogle Scholar
  171. 171.
    Weiner HL, Zagzag D. Growth factor receptor tyrosine kinases: cell adhesion kinase family suggests a novel signaling mechanism in cancer. Cancer Invest. 2000;18:544–554.PubMedCrossRefGoogle Scholar
  172. 172.
    Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1:433–443.PubMedCrossRefGoogle Scholar
  173. 173.
    Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61:7233–7239.PubMedGoogle Scholar
  174. 174.
    Wiener JR, Kassim SK, Yu Y, Mills GB, Bast RC, Jr. Transfection of human ovarian cancer cells with the HER-2/neu receptor tyrosine kinase induces a selective increase in PTP-H1, PTP-1B, PTP-alpha expression. Gynecol Oncol. 1996;61:233–240.PubMedCrossRefGoogle Scholar
  175. 175.
    Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–2439.PubMedCrossRefGoogle Scholar
  176. 176.
    Yamashita N, Osato M, Huang L, et al. Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice. Br J Haematol. 2005;131:495–507.PubMedCrossRefGoogle Scholar
  177. 177.
    Yee KW, O'Farrell AM, Smolich BD, et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood. 2002;100:2941–2949.PubMedCrossRefGoogle Scholar
  178. 178.
    Yee NS, Langen H, Besmer P. Mechanism of kit ligand, phorbol ester, and calcium-induced down-regulation of c-kit receptors in mast cells. J Biol Chem. 1993;268:14189–14201.PubMedGoogle Scholar
  179. 179.
    Yokota S, Kiyoi H, Nakao M, et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia. 1997;11:1605–1609.PubMedCrossRefGoogle Scholar
  180. 180.
    Zhao M, Kiyoi H, Yamamoto Y, et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia. 2000;14:374–378.PubMedCrossRefGoogle Scholar
  181. 181.
    Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004;103:267–274.PubMedCrossRefGoogle Scholar
  182. 182.
    Zwaan CM, Meshinchi S, Radich JP, et al. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Blood. 2003;102:2387–2394.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Clinical Research DivisionFrom Fred Hutchinson Cancer Research CenterSeattleUSA

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