Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

FLT3: ITDoes matter in leukemia

Abstract

FMS-like tyrosine kinase-3 (FLT3), a receptor tyrosine kinase, is important for the development of the hematopoietic and immune systems. Activating mutations of FLT3 are now recognized as the most common molecular abnormality in acute myeloid leukemia, and FLT3 mutations may play a role in other hematologic malignancies as well. The poor prognosis of patients harboring these mutations renders FLT3 an obvious target of therapy. This review summarizes the data on the molecular biology and clinical impact of FLT3 mutations, as well as the therapeutic potential of several small-molecule FLT3 inhibitors currently in development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Bishop JF . The treatment of adult acute myeloid leukemia. Semin Oncol 1997; 24: 57–69.

    CAS  PubMed  Google Scholar 

  2. Blume-Jensen P, Hunter T . Oncogenic kinase signalling. Nature 2001; 411: 355–365.

    CAS  PubMed  Google Scholar 

  3. Reilly JT . Class III receptor tyrosine kinases: role in leukaemogenesis. Br J Haematol 2002; 116: 744–757.

    CAS  PubMed  Google Scholar 

  4. Alexander WS, Nicola NA . Hemopoietic growth factor receptor abnormalities in leukemia. Leukemia Res 1998; 22: 1097–1111.

    CAS  Google Scholar 

  5. 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.

    CAS  PubMed  Google Scholar 

  6. 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.

    CAS  PubMed  Google Scholar 

  7. Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P et al. STK-1, the human homolog of Flk2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci USA 1994; 91: 459–463.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

    CAS  PubMed  Google Scholar 

  9. Blair A, Hogge DE, Sutherland HJ . Most acute myeloid leukemia progenitor cells with long-term proliferative ability in vitro and in vivo have the phenotype CD34(+)/CD71(−)/HLA-DR. Blood 1998; 92: 4325–4335.

    CAS  PubMed  Google Scholar 

  10. 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 

  11. Adolfsson J, Borge OJ, Bryder D, Theilgaard-Monch K, Astrand-Grundstrom I, Sitnicka E et al. Upregulation of Flt3 expression within the bone marrow Lin(−)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 2001; 15: 659–669.

    CAS  PubMed  Google Scholar 

  12. Christensen JL, Weissman IL . Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci USA 2001; 98: 14541–14546.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Nakao M, Yokota S, Iwai T, Kaneko H, Horiike S, Kashima K et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996; 10: 1911–1918.

    CAS  PubMed  Google Scholar 

  14. McKenna HJ . Role of hematopoietic growth factors/flt3 ligand in expansion and regulation of dendritic cells. Curr Opin Hematol 2001; 8: 149–154.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. 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.

    CAS  PubMed  Google Scholar 

  17. Carow CE, Kim E, Hawkins AL, Webb HD, Griffin CA, Jabs EW et al. Localization of the human stem cell tyrosine kinase-1 gene (FLT3) to 13q12–q13. Cytogenet Cell Genet 1995; 70: 255–257.

    CAS  PubMed  Google Scholar 

  18. 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.

    CAS  PubMed  Google Scholar 

  19. van der Geer P, Hunter T, Lindberg R . Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 1994; 10: 251–337.

    CAS  PubMed  Google Scholar 

  20. Lyman SD, James L, Vanden Bos T, de Vries P, Brasel K, Gliniak B et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993; 75: 1157–1167.

    CAS  PubMed  Google Scholar 

  21. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF 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.

    CAS  PubMed  Google Scholar 

  22. Lyman SD, James L, Johnson L, Brasel K, de Vries P, Escobar SS et al. Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 1994; 83: 2795–2801.

    CAS  PubMed  Google Scholar 

  23. Gotze KS, Ramirez M, Tabor K, Small D, Matthews W, Civin CI . Flt3high and Flt3low CD34+ progenitor cells isolated from human bone marrow are functionally distinct. Blood 1998; 91: 1947–1958.

    CAS  PubMed  Google Scholar 

  24. Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR . Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 1995; 3: 147–161.

    CAS  PubMed  Google Scholar 

  25. McKenna HJ, Stocking KL, Miller RE, Brasel K, De Smedt T, Maraskovsky E et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000; 95: 3489–3497.

    CAS  PubMed  Google Scholar 

  26. 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.

    CAS  PubMed  Google Scholar 

  27. Veiby OP, Jacobsen FW, Cui L, Lyman SD, Jacobsen SE . The flt3 ligand promotes the survival of primitive hemopoietic progenitor cells with myeloid as well as B lymphoid potential. Suppression of apoptosis and counteraction by TNF-alpha and TGF-beta. J Immunol 1996; 157: 2953–2960.

    CAS  PubMed  Google Scholar 

  28. Broxmeyer HE, Lu L, Cooper S, Ruggieri L, Li ZH, Lyman SD . Flt3 ligand stimulates/costimulates the growth of myeloid stem/progenitor cells. Exp Hematol 1995; 23: 1121–1129.

    CAS  PubMed  Google Scholar 

  29. Hirayama F, Lyman SD, Clark SC, Ogawa M . The flt3 ligand supports proliferation of lymphohematopoietic progenitors and early B-lymphoid progenitors. Blood 1995; 85: 1762–1768.

    CAS  PubMed  Google Scholar 

  30. Nicholls SE, Mottram R, Miyan JA, Whetton AD . Flt3 ligand can promote survival and macrophage development without proliferation in myeloid progenitor cells. Exp Hematol 1999; 27: 663–672.

    CAS  PubMed  Google Scholar 

  31. Sitnicka E, Buza-Vidas N, Larsson S, Nygren JM, Liuba K, Jacobsen SE . Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells. Blood 2003 (in press).

  32. Dosil M, Wang S, Lemischka IR . Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Mol Cell Biol 1993; 13: 6572–6585.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosnet O, Buhring HJ, deLapeyriere O, Beslu N, Lavagna C, Marchetto S et al. Expression and signal transduction of the FLT3 tyrosine kinse receptor. Acta Haematol 1996; 95: 218–223.

    CAS  PubMed  Google Scholar 

  34. Lavagna-Sevenier C, Marchetto S, Birnbaum D, Rosnet O . FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Leukemia 1998; 12: 301–310.

    CAS  PubMed  Google Scholar 

  35. Zhang S, Mantel C, Broxmeyer HE . Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells. J Leukocyte Biol 1999; 65: 372–380.

    CAS  PubMed  Google Scholar 

  36. Marchetto S, Fournier E, Beslu N, Aurran-Schleinitz T, Dubreuil P, Borg JP et al. SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia 1999; 13: 1374–1382.

    CAS  PubMed  Google Scholar 

  37. Zhang S, Fukuda S, Lee Y, Hangoc G, Cooper S, Spolski R et al. Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. J Exp Med 2000; 192: 719–728.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Meierhoff G, Dehmel U, Gruss HJ, Rosnet O, Birnbaum D, Quentmeier H et al. Expression of FLT3 receptor and FLT3-ligand in human leukemia-lymphoma cell lines. Leukemia 1995; 9: 1368–1372.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Zheng R, Levis M, Piloto O, Brown P, Baldwin BR, Gorin NC et al. FLT3 ligand (FL) causes autocrine signaling in AML cells. 2003 (submitted).

  41. Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 1996; 87: 1089–1096.

    CAS  PubMed  Google Scholar 

  42. Birg F, Courcoul M, Rosnet O, Bardin F, Pebusque MJ, Marchetto S et al. Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood 1992; 80: 2584–2593.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  44. Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 2003; 3: 173–183.

    CAS  PubMed  Google Scholar 

  45. Piacibello W, Fubini L, Sanavio F, Felice-Brizzi M, Severino A, Garelto L et al. Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors. Blood 1995; 86: 4105–4114.

    CAS  PubMed  Google Scholar 

  46. Lisovsky M, Estrov Z, Zhang X, Consoli U, Sanchez-Williams G, Snell V et al. Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. Blood 1996; 88: 3987–3997.

    CAS  PubMed  Google Scholar 

  47. Stacchini A, Fubini L, Severino A, Sanavio F, Aglietta M, Piacibello W . Expression of type III receptor tyrosine kinases FLT3 and KIT and responses to their ligands by acute myeloid leukemia blasts. Leukemia 1996; 10: 1584–1591.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  49. Braun SE, Aronica SM, Ge Y, Takahira H, Etienne-Julan M, Lu L et al. Retroviral mediated gene transfer of Flt3 ligand enhances proliferation and MAP kinase activity of AML5 cells. Exp Hematol 1997; 25: 51–56.

    CAS  PubMed  Google Scholar 

  50. Brasel K, Escobar S, Anderberg R, de Vries P, Gruss HJ, Lyman SD . Expression of the flt3 receptor and its ligand on hematopoietic cells. Leukemia 1995; 9: 1212–1218.

    CAS  PubMed  Google Scholar 

  51. Solanilla A, Grosset C, Lemervier C, Dupouy M, Mahon F, Schweitzer K et al. Expression of Flt3-ligand by the endothelial cell. Leukemia 2000; 14: 153–162.

    CAS  PubMed  Google Scholar 

  52. Hawley TS, Fong AZ, Griesser H, Lyman SD, Hawley RG . Leukemic predisposition of mice transplanted with gene-modified hematopoietic precursors expressing flt3 ligand. Blood 1998; 92: 2003–2011.

    CAS  PubMed  Google Scholar 

  53. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–2439.

    CAS  PubMed  Google Scholar 

  54. 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.

    CAS  PubMed  Google Scholar 

  55. Horiike S, Yokota S, Nakao M, Iwai T, Sasai Y, Kaneko H et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia 1997; 11: 1442–1446.

    CAS  PubMed  Google Scholar 

  56. Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia 1997; 11: 1447–1452.

    CAS  PubMed  Google Scholar 

  57. Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080.

    CAS  PubMed  Google Scholar 

  58. Nakano Y, Kiyoi H, Miyawaki S, Asou N, Ohno R, Saito H et al. Molecular evolution of acute myeloid leukaemia in relapse: unstablesN-ras and FLT3 genes compared with p53 gene. Br J Haematol 1999; 104: 659–664.

    CAS  PubMed  Google Scholar 

  59. 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.

    CAS  PubMed  Google Scholar 

  60. Abu-Duhier FM, Goodeve AC, Wilson GA, Gari MA, Peake IR, Rees DC et al. FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol 2000; 111: 190–195.

    CAS  PubMed  Google Scholar 

  61. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97: 3589–3595.

    CAS  PubMed  Google Scholar 

  62. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA 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.

    CAS  PubMed  Google Scholar 

  63. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD 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.

    CAS  PubMed  Google Scholar 

  64. Iwai T, Yokota S, Nakao M, Okamoto T, Taniwaki M, Onodera N 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.

    CAS  PubMed  Google Scholar 

  65. Xu F, Taki T, Yang HW, Hanada R, Hongo T, Ohnishi H 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.

    CAS  PubMed  Google Scholar 

  66. Kondo M, Horibe K, Takahashi Y, Matsumoto K, Fukuda M, Inaba J et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol 1999; 33: 525–529.

    CAS  PubMed  Google Scholar 

  67. Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 2001; 97: 89–94.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  69. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U 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.

    CAS  PubMed  Google Scholar 

  70. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C 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.

    CAS  PubMed  Google Scholar 

  71. Boissel N, Cayuela JM, Preudhomme C, Thomas X, Grardel N, Fund X et al. Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy. Leukemia 2002; 16: 1699–1704.

    CAS  PubMed  Google Scholar 

  72. Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 2002; 16: 2185–2189.

    CAS  PubMed  Google Scholar 

  73. Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K 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.

    CAS  PubMed  Google Scholar 

  74. Kainz B, Heintel D, Marculescu R, Schwarzinger I, Sperr W, Le T et al. Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16). Hematol J 2002; 3: 283–289.

    CAS  PubMed  Google Scholar 

  75. Moreno I, Martin G, Bolufer P, Barragan E, Rueda E, Roman J et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica 2003; 88: 19–24.

    CAS  PubMed  Google Scholar 

  76. Jilani I, Estey E, Manshuri T, Caligiuri M, Keating M, Giles F et al. Better detection of FLT3 internal tandem duplication using peripheral blood plasma DNA. Leukemia 2003; 17: 114–119.

    CAS  PubMed  Google Scholar 

  77. Arrigoni P, Beretta C, Silvestri D, Rossi V, Rizzari C, Valsecchi MG et al. FLT3 internal tandem duplication in childhood acute myeloid leukaemia: association with hyperleucocytosis in acute pro-myelocytic leukaemia. Br J Haematol 2003; 120: 89–92.

    CAS  PubMed  Google Scholar 

  78. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T 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.

    CAS  PubMed  Google Scholar 

  79. Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 2002; 99: 3885–3891.

    CAS  PubMed  Google Scholar 

  80. Quentmeier H, Reinhardt J, Zaborski M, Drexler HG . FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 2003; 17: 120–124.

    CAS  PubMed  Google Scholar 

  81. Ma Y, Longley BJ, Wang X, Blount JL, Caughey GH . Clustering of activating mutations in c-KIT's juxtamembrane coding region in canine mast cell neoplasms. J Invest Dermatol 1999; 112: 165–170.

    CAS  PubMed  Google Scholar 

  82. Chia W, Savakis C, Karp R, Pelham H, Ashburner M . Mutation of the Adh gene of Drosophila melanogaster containing an internal tandem duplication. J Mol Biol 1985; 186: 679–688.

    CAS  PubMed  Google Scholar 

  83. Jamal R, Taketani T, Taki T, Bessho F, Hongo T, Hamaguchi H et al. Coduplication of the MLL and FLT3 genes in patients with acute myeloid leukemia. Genes Chromosomes Cancer 2001; 31: 187–190.

    CAS  PubMed  Google Scholar 

  84. Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res 1998; 58: 55–59.

    CAS  PubMed  Google Scholar 

  85. Whitman SP, Strout MP, Marcucci G, Freud AG, Culley LL, Zeleznik-Le NJ et al. The partial nontandem duplication of the MLL (ALL1) gene is a novel rearrangement that generates three distinct fusion transcripts in B-cell acute lymphoblastic leukemia. Cancer Res 2001; 61: 59–63.

    CAS  PubMed  Google Scholar 

  86. Shiah HS, Kuo YY, Tang JL, Huang SY, Yao M, Tsay W et al. Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23. Leukemia 2002; 16: 196–202.

    CAS  PubMed  Google Scholar 

  87. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H 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.

    CAS  PubMed  Google Scholar 

  88. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito 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.

    CAS  PubMed  Google Scholar 

  89. Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C 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.

    CAS  PubMed  Google Scholar 

  90. Tse K-F, 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.

    CAS  PubMed  Google Scholar 

  91. 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.

    CAS  PubMed  Google Scholar 

  92. Fenski R, Flesch K, Serve S, Mizuki M, Oelmann E, Kratz-Albers K 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.

    CAS  PubMed  Google Scholar 

  93. 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.

    CAS  PubMed  Google Scholar 

  94. Wybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F . Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 2001; 106: 745–757.

    CAS  PubMed  Google Scholar 

  95. Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J . The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell 2001; 8: 671–682.

    CAS  PubMed  Google Scholar 

  96. Hubbard SR . Theme and variations: juxtamembrane regulation of receptor protein kinases. Mol Cell 2001; 8: 481–482.

    CAS  PubMed  Google Scholar 

  97. Irusta PM, DiMaio D . A single amino acid substitution in a WW-like domain of diverse members of the PDGF receptor subfamily of tyrosine kinases causes constitutive receptor activation. EMBO J 1998; 17: 6912–6923.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Tsujimura T, Morimoto M, Hashimoto K, Moriyama Y, Kitayama H, Matsuzawa Y 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.

    CAS  PubMed  Google Scholar 

  99. Ma Y, Cunningham ME, Wang X, Ghosh I, Regan L, Longley BJ . Inhibition of spontaneous receptor phosphorylation by residues in a putative alpha-helix in the KIT intracellular juxtamembrane region. J Biol Chem 1999; 274: 13399–13402.

    CAS  PubMed  Google Scholar 

  100. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998; 279: 577–580.

    CAS  PubMed  Google Scholar 

  101. Tse KF, Mukherjee G, Small D . Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia 2000; 14: 1766–1776.

    CAS  PubMed  Google Scholar 

  102. Zheng R, Friedman AD, Small D . Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. Blood 2002; 100: 4154–4161.

    CAS  PubMed  Google Scholar 

  103. Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 2003; 101: 3164–3173.

    CAS  PubMed  Google Scholar 

  104. Kim K, Baird K, Allebach J, Meltzer P, Small D . Pim-1 and Myc expressions are remarkably decreased in response to FLT3 inhibitor in FLT3-expressing leukemia cells. Blood 2002; 100: 138a.

    Google Scholar 

  105. Lumkul R, Gorin NC, Malehorn MT, Hoehn GT, Zheng R, Baldwin B et al. Human AML cells in NOD/SCID mice: engraftment potential and gene expression. Leukemia 2002; 16: 1818–1826.

    CAS  PubMed  Google Scholar 

  106. Rombouts WJ, Broyl A, Martens AC, Slater R, Ploemacher RE . Human acute myeloid leukemia cells with internal tandem duplications in the Flt3 gene show reduced proliferative ability in stroma supported long-term cultures. Leukemia 1999; 13: 1071–1078.

    CAS  PubMed  Google Scholar 

  107. Rombouts W, Martens A, Ploemacher R . Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model. Leukemia 2000; 14: 889–897.

    CAS  PubMed  Google Scholar 

  108. O'Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101: 3597–3605.

    CAS  PubMed  Google Scholar 

  109. Baldwin BR, Tse K-F, Small D . Transgenic mice expressing a constitutively activated FLT3 receptor display a myeloproliferative disease phenotype. Blood 2001; 98: 801a.

    Google Scholar 

  110. 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.

    CAS  PubMed  Google Scholar 

  111. Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Sohal J, Phan VT, Chan PV, Davis EM, Patel B, Kelly LM et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Blood 2003; 101: 3188–3197.

    CAS  PubMed  Google Scholar 

  113. Le Beau MM, Davis EM, Patel B, Phan VT, Sohal J, Kogan SC . Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia. Blood 2003.

  114. Xu F, Taki T, Eguchi M, Kamada N, Ishii E, Endo 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.

    CAS  PubMed  Google Scholar 

  115. Christiansen DH, Pedersen-Bjergaard J . Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy. Leukemia 2001; 15: 1848–1851.

    CAS  PubMed  Google Scholar 

  116. Abu-Duhier FM, Goodeve AC, Care RS, Gari M, Wilson GA, Peake IR et al. Mutational analysis of class III receptor tyrosine kinases (C-KIT, C-FMS, FLT3) in idiopathic myelofibrosis. Br J Haematol 2003; 120: 464–470.

    CAS  PubMed  Google Scholar 

  117. Abu-Duhier FM, Goodeve AC, Wilson GA, Carr RS, Peake IR, Reilly JT . FLT3 internal tandem duplication mutations are rare in agnogenic myeloid metaplasia. Blood 2002; 100: 364.

    CAS  PubMed  Google Scholar 

  118. Haferlach T, Schoch C, Schnittger S, Kern W, Loffler H, Hiddemann W . Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients. Br J Haematol 2002; 118: 426–431.

    CAS  PubMed  Google Scholar 

  119. Strout MP, Marcucci G, Caligiuri MA, Bloomfield CD . Core-binding factor (CBF) and MLL-associated primary acute myeloid leukemia: biology and clinical implications. Ann Hematol 1999; 78: 251–264.

    CAS  PubMed  Google Scholar 

  120. Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood 2002; 100: 2387–2392.

    CAS  PubMed  Google Scholar 

  121. 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.

    CAS  PubMed  Google Scholar 

  122. Till JH, Ablooglu AJ, Frankel M, Bishop SM, Kohanski RA, Hubbard SR . Crystallographic and solution studies of an acti-vation loop mutant of the insulin receptor tyrosine kinase: insights into kinase mechanism. J Biol Chem 2001; 276: 10049–10055.

    CAS  PubMed  Google Scholar 

  123. Furitsu T, Tsujimura T, Tono T, Ikeda H, Kitayama H, Koshimizu U 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Jeffers M, Schmidt L, Nakaigawa N, Webb CP, Weirich G, Kishida T et al. Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA 1997; 94: 11445–11450.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M et al. Activation of RET as a dominant transforming gene by Germline Mutations of MEN2A and MEN2B. Science 1995; 267: 381–383.

    CAS  PubMed  Google Scholar 

  126. Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E et al. C-kit mutations in core binding factor leukemias. Blood 2000; 95: 726–727.

    CAS  PubMed  Google Scholar 

  127. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y 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: 10560–10564.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 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.

    CAS  PubMed  Google Scholar 

  129. Bloomfield CD, Goldman A, Hassfeld D, de la Chapelle A . Fourth International Workshop on Chromosomes in Leukemia 1982: clinical significance of chromosomal abnormalities in acute nonlymphoblastic leukemia. Cancer Genet Cytogenet 1984; 11: 332–350.

    CAS  PubMed  Google Scholar 

  130. Radich JP, Kopecky KJ, Willman CL, Weick J, Head D, Appelbaum F et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 1990; 76: 801–807.

    CAS  PubMed  Google Scholar 

  131. Neubauer A, Dodge RK, George SL, Davey FR, Silver RT, Schiffer CA et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 1994; 83: 1603–1611.

    CAS  PubMed  Google Scholar 

  132. Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E et al. C-kit mutations in core binding factor leukemias. Blood 2000; 95: 726–727.

    CAS  PubMed  Google Scholar 

  133. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Hortobagyi GN . Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. Semin Oncol 2001; 28: 43–47.

    CAS  PubMed  Google Scholar 

  135. Radich JP . Philadelphia chromosome-positive acute lymphocytic leukemia. Hematol Oncol Clin N Am 2001; 15: 21–36.

    CAS  Google Scholar 

  136. Hayes DF, Thor AD . c-erbB-2 in breast cancer: development of a clinically useful marker. Semin Oncol 2002; 29: 231–245.

    CAS  PubMed  Google Scholar 

  137. Druker B, Sawyers C, Kantarjian H, Resta D, Reese S, Ford J 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.

    CAS  PubMed  Google Scholar 

  138. Tse KF, Novelli E, Civin CI, Bohmer FD, Small D . Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. Leukemia 2001; 15: 1001–1010.

    CAS  PubMed  Google Scholar 

  139. 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.

    CAS  PubMed  Google Scholar 

  140. Gazit A, App H, McMahon G, Chen J, Levitzki A, Bohmer F . Tyrphostins. 5. Potent inhibitors of platelet-derived growth factor receptor tyrosine kinase: structure–activity relationships in quinoxalines, quinolines, and indole tyrphostins. J Med Chem 1996; 39: 2170–2177.

    CAS  PubMed  Google Scholar 

  141. Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 2002; 1: 433–443.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  143. Teller S, Kramer D, Bohmer SA, Tse KF, Small D, Mahboobi S et al. Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. Leukemia 2002; 16: 1528–1534.

    CAS  PubMed  Google Scholar 

  144. Yee KW, O'Farrell AM, Smolich BD, Cherrington JM, McMahon G, Wait CL et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 2002; 100: 2941–2949.

    CAS  PubMed  Google Scholar 

  145. Gazit A, Yee K, Uecker A, Bohmer FD, Sjoblom T, Ostman A et al. Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. Bioorg Med Chem 2003; 11: 2007–2018.

    CAS  PubMed  Google Scholar 

  146. Spiekermann K, Dirschinger RJ, Schwab R, Bagrintseva K, Faber F, Buske C et al. The protein tyrosine kinase inhibitor SU5614 inhibits FLT3 and induces growth arrest and apoptosis in AML-derived cell lines expressing a constitutively activated FLT3. Blood 2003; 101: 1494–1504.

    CAS  PubMed  Google Scholar 

  147. Lamers MB, Antson AA, Hubbard RE, Scott RK, Williams DH . Structure of the protein tyrosine kinase domain of C-terminal Src kinase (CSK) in complex with staurosporine. J Mol Biol 1999; 285: 713–725.

    CAS  PubMed  Google Scholar 

  148. Bohmer FD, Karagyozov L, Uecker A, Serve H, Botzki A, Mahboobi S et al. A single amino acid exchange inverts susceptibility of related receptor tyrosine kinases for the ATP site inhibitor STI-571. J Biol Chem 2003; 278: 5148–5155.

    PubMed  Google Scholar 

  149. Stone RM, Klimeck V, DeAngelo D, Nimer S, Estey E, Galinsky I et al. PKC412, an oral FLT3 inhibitor, has activity in mutant FLT3 acute myeloid leukemia (AML): a phase II clinical trial. Blood 2002; 100: 86a.

    Google Scholar 

  150. Foran J, Paquette R, Cooper M, Jacobs M, O'Farrell A-M, Kim H 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: 558a.

    Google Scholar 

  151. Heinrich M, Druker B, Curtin P, Paquette R, Sawyers C, DeAngelo D et al. A ‘first in man’ study of the safety and PK/PD of an oral FLT3 inhibitor (MLN518) in ptients with AML or high risk myelodysplasia. Blood 2002; 100: 336a.

    Google Scholar 

  152. Whitman SP, Guimond M, Blaser B, Klisovic M, Vukosavlejevic T, Bruner R et al. Primary acute myeloid leukemia (AML) cells with the FLT3 internal tandem duplication (ITD) and absence of wild type (WT) FLT3 (FLT3ITD/− genotype) are distinct from AML with either FLT3wt/wtor FLT3ITD/wt genotypes. Blood 2002; 100: 89a.

    Google Scholar 

  153. Smith BD, Levis M, Brown P, Russell L, Hellreigel E, Dauses T et al. Single agent CEP-701, a novel FLT-3 inhibitor, shows initial response in patients with refractory acute myeloid leukemia. Blood 2002; 100: 85a.

    Google Scholar 

  154. Ross DD . Novel mechanisms of drug resistance in leukemia. Leukemia 2000; 14: 467–473.

    CAS  PubMed  Google Scholar 

  155. Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.

    CAS  PubMed  Google Scholar 

  156. Rombouts WJ, Martens AC, Ploemacher RE . Identification of variables determining the engraftment potential of human acute myeloid leukemia in the immunodeficient NOD/SCID human chimera model. Leukemia 2000; 14: 889–897.

    CAS  PubMed  Google Scholar 

  157. Murphy KM, Levis M, Hafez MJ, Geiger T, Cooper LC, Smith BD et al. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn 2003; 5: 96–102.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NCI (1K08CA95600-01A1, ML; CA70970 and CA91177, DS), the Sidney Kimmel Foundation for Cancer Research (ML), The American Society of Clinical Onoclogy (ML) D.S. is the Douglas Kroll Research Foundation Translations/Researcher of the Leukemia and Lymphoma Society and The Children's Cancer Foundation (DS).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levis, M., Small, D. FLT3: ITDoes matter in leukemia. Leukemia 17, 1738–1752 (2003). https://doi.org/10.1038/sj.leu.2403099

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403099

Keywords

This article is cited by

Search

Quick links