Skip to main content
SpringerLink
Log in

Biology, Clinical Relevance, and Molecularly Targeted Therapy in Acute Leukemia with Flt3 Mutation

  • Progress in Hematology
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Overexpression and activating mutations of receptor tyrosine kinases (RTKs) are known to be involved in the pathophys-iology of several kinds of cancer cells. FMS-like receptor tyrosine kinase 3 (FLT3), together with KIT, FMS, and platelet-derived growth factor receptor, is a class III RTK. FLT3 mutations were first reported as internal tandem duplication (FLT3/ ITD) of the juxtamembrane domain-coding sequence; subsequently, a missense point mutation at the D835 residue and point mutations, deletions, and insertions in the codons surrounding D835 within a FLT3 tyrosine kinase domain (FLT3/KDMs) have been found. FLT3 mutations are the most frequent genetic alterations so far reported in acute myeloid leukemia and are involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis.Therefore, routine screening for FLT3 mutations is recommended to stratify patients into distinct risk groups. However, because high-dose chemotherapy and stem cell transplantation cannot overcome the adverse effects of FLT3 mutations, the development of FLT3 kinase inhibitors is expected to produce a more efficacious therapeutic strategy for leukemia therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene. 1991;6:1641–1650.

    PubMed  CAS  Google Scholar 

  2. Rosnet O, Schiff C, Pebusque MJ, et al. Human FLT3/FLK2 gene:cDNA cloning and expression in hematopoietic cells. Blood. 1993;82:1110–1119.

    PubMed  CAS  Google Scholar 

  3. Lyman SD, James L, Zappone J, Sleath PR, Beckmann MP, Bird T. Characterization of the protein encoded by the flt3 (flk2) receptorlike tyrosine kinase gene. Oncogene. 1993;8:815–822.

    PubMed  CAS  Google Scholar 

  4. Matthews W, Jordan CT,Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991;65:1143–1152.

    Article  CAS  PubMed  Google Scholar 

  5. Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Genomic structure of human FLT3: implications for mutational analysis. Br J Haematol. 2001;113:1076–1077.

    Article  CAS  PubMed  Google Scholar 

  6. Lyman SD. Biology of flt3 ligand and receptor. Int J Hematol. 1995;62:63–73.

    Article  CAS  PubMed  Google Scholar 

  7. Rosnet O, Buhring HJ, deLapeyriere O, et al. Expression and signal transduction of the FLT3 tyrosine kinase receptor. Acta Haematol. 1996;95:218–223.

    Article  CAS  PubMed  Google Scholar 

  8. Hannum C, Culpepper J, Campbell D, et al. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature. 1994;368:643–648.

    Article  CAS  PubMed  Google Scholar 

  9. McKenna HJ, Smith FO, Brasel K, et al. Effects of flt3 ligand on acute myeloid and lymphocytic leukemic blast cells from children. Exp Hematol. 1996;24:378–385.

    PubMed  CAS  Google Scholar 

  10. 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.

    PubMed  CAS  Google Scholar 

  11. Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood. 1998;91:1101–1134.

    CAS  PubMed  Google Scholar 

  12. Dehmel U, Zaborski M, Meierhoff G, et al. Effects of FLT3 ligand on human leukemia cells, I: proliferative response of myeloid leukemia cells. Leukemia. 1996;10:261–270.

    PubMed  CAS  Google Scholar 

  13. Dehmel U, Quentmeier H, Drexler HG. Effects of FLT3 ligand on human leukemia cells, II: agonistic and antagonistic effects of other cytokines. Leukemia. 1996;10:271–278.

    PubMed  CAS  Google Scholar 

  14. DaSilva N, Hu ZB, Ma W, Rosnet O, Birnbaum D, Drexler HG. Expression of the FLT3 gene in human leukemia-lymphoma cell lines. Leukemia. 1994;8:885–888.

    PubMed  CAS  Google Scholar 

  15. Drexler HG. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia. 1996;10:588–599.

    PubMed  CAS  Google Scholar 

  16. Drexler HG, Meyer C, Quentmeier H. Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells. Leuk Lym-phoma. 1999;33:83–91.

    Article  CAS  Google Scholar 

  17. Rosnet O, Buhring HJ, Marchetto S, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996;10:238–248.

    PubMed  CAS  Google Scholar 

  18. Zheng R, Levis M, Piloto O, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004;103:267–274.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    PubMed  CAS  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    CAS  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. Spiekermann K, Bagrintseva K, Schoch C, Haferlach T, Hidde-mann 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. Taketani T,Taki T, Sugita K, et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood. 2004;103:1085–1088.

    Article  CAS  PubMed  Google Scholar 

  27. Kiyoi H, Naoe T. FLT3 in human hematologic malignancies. Leuk Lymphoma. 2002;43:1541–1547.

    Article  CAS  PubMed  Google Scholar 

  28. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–665.

    Article  CAS  PubMed  Google Scholar 

  29. Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17:1738–1752.

    Article  CAS  PubMed  Google Scholar 

  30. Kottaridis PD, Gale RE, Linch DC. Flt3 mutations and leukaemia. Br J Haematol. 2003;122:523–538.

    Article  CAS  PubMed  Google Scholar 

  31. Naoe T, Kiyoi H. Normal and oncogenic FLT3. Cell Mol Life Sci. 2004;61:2932–2938.

    Article  CAS  PubMed  Google Scholar 

  32. Kiyoi H, Yanada M, Ozekia K. Clinical significance of FLT3 in leukemia. Int J Hematol. 2005;82:85–92.

    Article  CAS  PubMed  Google Scholar 

  33. Ozeki K, Kiyoi H, Hirose Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood. 2004;103:1901–1908.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Kiyoi H, Naoe T. FLT3 mutations in acute myeloid leukemia. Methods Mol Med. 2006;125:189–197.

    PubMed  CAS  Google Scholar 

  36. Libura M, Asnafi V, Tu A, et al. FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. Blood. 2003;102:2198–2204.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    PubMed  CAS  Google Scholar 

  39. Weiss A, Schlessinger J. Switching signals on or off by receptor dimerization. Cell. 1998;94:277–280.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. Morley GM, Uden M, Gullick WJ, Dibb NJ. Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation. Oncogene. 1999;18:3076–3084.

    Article  CAS  PubMed  Google Scholar 

  42. Bianchini M, Ottaviani E, Grafone T, et al. Rapid detection of Flt3 mutations in acute myeloid leukemia patients by denaturing HPLC. Clin Chem. 2003;49:1642–1650.

    Article  CAS  PubMed  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Article  CAS  PubMed  Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. Zheng R, Friedman AD, Levis M, Li L, Weir EG, Small D Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression. Blood. 2004;103:1883–1890.

    Article  CAS  PubMed  Google Scholar 

  49. Griffith J, Black J, Faerman C, et al. The structural basis for autoin-hibition of FLT3 by the juxtamembrane domain. Mol Cell. 2004;13:169–178.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. Kelly LM, Kutok JL, Williams IR, et al. PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci U S A.2002;99:8283–8288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Horiike S, Yokota S, Nakao M, et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia. 1997;11:1442–1446.

    Article  CAS  PubMed  Google Scholar 

  53. Rombouts WJ, Blokland I, Lowenberg B, Ploemacher RE. Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia. 2000;14:675–683.

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. 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.

    Article  CAS  PubMed  Google Scholar 

  57. 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.

    Article  CAS  PubMed  Google Scholar 

  58. Xu F, Taki T, Yang HW, et al. Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children. Br J Haematol.1999;105:155–162.

    Article  CAS  PubMed  Google Scholar 

  59. Kondo M, Horibe K, Takahashi Y, et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myel-ogenous leukemia. Med Pediatr Oncol. 1999;33:525–529.

    Article  CAS  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

  61. Liang DC, Shih LY, Hung IJ, et al. Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia. Cancer. 2002;94:3292–3298.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. Arrigoni P, Beretta C, Silvestri D, et al. FLT3 internal tandem duplication in childhood acute myeloid leukaemia: association with hyperleucocytosis in acute promyelocytic leukaemia. Br J Haematol. 2003;120:89–92.

    Article  CAS  PubMed  Google Scholar 

  64. Xu F, Taki T, Eguchi M, et al. Tandem duplication of the FLT3 gene is infrequent in infant acute leukemia: Japan Infant Leukemia Study Group. Leukemia. 2000;14:945–947.

    Article  CAS  PubMed  Google Scholar 

  65. Kiyoi H, Naoe T, Yokota S, et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia: Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia. 1997;11:1447–1452.

    Article  CAS  PubMed  Google Scholar 

  66. 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.

    PubMed  CAS  Google Scholar 

  67. Falini B, Mecucci C, Tiacci E, et al, for the GIMEMA Acute Leukemia Working Party. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–266.

    Article  CAS  PubMed  Google Scholar 

  68. Suzuki T, Kiyoi H, Ozeki K, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood. 2005;106:2854–2861.

    Article  CAS  PubMed  Google Scholar 

  69. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19:1345–1349.

    Article  CAS  PubMed  Google Scholar 

  70. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2005;106:3658–3665.

    Article  CAS  PubMed  Google Scholar 

  71. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2:502–513.

    Article  CAS  PubMed  Google Scholar 

  72. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. In press.

  73. Verhaak RG, Goudswaard CS, van Putten W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106:3747–3754.

    Article  CAS  PubMed  Google Scholar 

  74. Dohner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740–3746.

    Article  CAS  PubMed  Google Scholar 

  75. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733–3739.

    Article  CAS  PubMed  Google Scholar 

  76. Boissel N, Renneville A, Biggio V, et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood. 2005;106:3618–3620.

    Article  CAS  PubMed  Google Scholar 

  77. Borer RA, Lehner CF, Eppenberger HM, Nigg EA. Major nucleo-lar proteins shuttle between nucleus and cytoplasm. Cell. 1989;56:379–390.

    Article  CAS  PubMed  Google Scholar 

  78. Chan WY, Liu QR, Borjigin J, et al. Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growth. Biochemistry. 1989;28:1033–1039.

    Article  CAS  PubMed  Google Scholar 

  79. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 1994;263:1281–1284.

    Article  CAS  PubMed  Google Scholar 

  80. Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophos-min-retinoic acid receptor fusion. Blood. 1996;87:882–886.

    PubMed  CAS  Google Scholar 

  81. Yoneda-Kato N, Look AT, Kirstein MN, et al. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene. 1996;12:265–275.

    PubMed  CAS  Google Scholar 

  82. Szebeni A, Olson MO. Nucleolar protein B23 has molecular chaperone activities. Protein Sci. 1999;8:905–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG. Nucle-ophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol. 2002;4:529–533.

    Article  CAS  PubMed  Google Scholar 

  84. Kurki S, Peltonen K, Laiho M. Nucleophosmin, HDM2 and p53: players in UV damage incited nucleolar stress response. Cell Cycle. 2004;3:976–979.

    Article  CAS  PubMed  Google Scholar 

  85. Grisendi S, Pandolfi PP. NPM mutations in acute myelogenous leukemia. N Engl J Med. 2005;352:291–292.

    Article  CAS  PubMed  Google Scholar 

  86. Levis M, Small D. FLT3 tyrosine kinase inhibitors. Int J Hematol. 2005;82:100–107.

    Article  CAS  PubMed  Google Scholar 

  87. Pandey A, Volkots DL, Seroogy JM, et al. Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem. 2002;45:3772–3793.

    Article  CAS  PubMed  Google Scholar 

  88. Kelly LM, Yu JC, Boulton CL, et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell. 2002;1:421–432.

    Article  CAS  PubMed  Google Scholar 

  89. DeAngelo 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 [abstract]. Blood. 2004;104. Abstract 1792.

    Google Scholar 

  90. Meyer T, Regenass U, Fabbro D, et al. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer. 1989;43:851–856.

    Article  CAS  PubMed  Google Scholar 

  91. 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.

    Article  CAS  PubMed  Google Scholar 

  92. 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.

    Article  CAS  PubMed  Google Scholar 

  93. George DJ, Dionne CA, Jani J, et al. Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). Cancer Res. 1999;59:2395–2401.

    PubMed  CAS  Google Scholar 

  94. 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.

    Article  CAS  PubMed  Google Scholar 

  95. 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.

    Article  CAS  PubMed  Google Scholar 

  96. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood. 2004;104:1145–1150.

    Article  CAS  PubMed  Google Scholar 

  97. Fiedler W, Serve H, Dohner H, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105:986–993.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8560, Nagoya, Japan

    Hitoshi Kiyoi

  2. Departments of Hematology/Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tomoki Naoe

Authors
  1. Hitoshi Kiyoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoki Naoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hitoshi Kiyoi.

About this article

Cite this article

Kiyoi, H., Naoe, T. Biology, Clinical Relevance, and Molecularly Targeted Therapy in Acute Leukemia with Flt3 Mutation. Int J Hematol 83, 301–308 (2006). https://doi.org/10.1532/IJH97.06071

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1532/IJH97.06071

Key words

Search

Navigation