Advertisement

Medical Oncology

, Volume 20, Issue 4, pp 311–323 | Cite as

Flt3 in acute myelogenous leukemia

Biology, prognosis, and therapeutic implications
Review Article

Abstract

Flt3 is a tyrosine kinase receptor expressed on hematopoietic cells. Activating mutations of this receptor are encountered in over one-fourth of acute myelogenous leukemia (AML) cases and activate multiple intracellular pathways leading to cell proliferation, inhibition of apoptosis, and blockage of differentiation in leukemic blasts. AML with flt3 mutations has a worse prognosis than AML with normal flt3, at least in younger patients. Sevaral flt3 inhibitors are in various stages of preclinical and clinical development and it is hoped that specific therapies against AML with flt3 mutations will soon be available to the clinician.

Key Words

Flt3 mutations acute myelogenous leukemia (AML) prognosis treatment 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gilliland, D.G. and Griffin, J.D. (2002). The roles of FLT3 in hematopoiesis and leukemia. Blood 100:1532–1542.PubMedCrossRefGoogle Scholar
  2. 2.
    Kiyoi, H. and Naoe, T. (2002). FLT3 in human hematologic malignancies. Leuk. Lymphoma 43:1541–1547.PubMedCrossRefGoogle Scholar
  3. 3.
    Testa, U., et al. (2002). Human acute stem cell leukemia with multilineage differentiation potential via cascade activation of growth factor receptors. Blood 99:4634–4637.PubMedCrossRefGoogle Scholar
  4. 4.
    Tse, K.F., Mukherjee, G. and Small, D. (2000). Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation. Leukemia 14:1766–1776.PubMedCrossRefGoogle Scholar
  5. 5.
    Matthews, W., Jordan, C.T., Wiegand, G.W., Pardoll, D. and Lemischka, I.R. (1991). A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 65:1143–1152.PubMedCrossRefGoogle Scholar
  6. 6.
    Rosnet, O., Marchetto, S., deLapeyriere, O., and Birnbaum, D. (1991). Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 6:1641–1650.PubMedGoogle Scholar
  7. 7.
    Lyman, S.D., et al. (1993). Characterization of the protein encoded by the flt3 (flk2) receptor-like tyrosine kinase gene. Oncogene 8:815–822.PubMedGoogle Scholar
  8. 8.
    Abu-Duhier, F.M., et al. (2001). Genomic structure of human FLT3: implications for mutational analysis. Br. J. Haematol. 113:1076–1077.PubMedCrossRefGoogle Scholar
  9. 9.
    Lyman, S.D. and Jacobsen, S.E. (1998). c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 91:1101–1134.PubMedGoogle Scholar
  10. 10.
    Christensen, J.L. and Weissman, I.L. (2001). Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl. Acad. Sci. USA 98:14,541–14,546.Google Scholar
  11. 11.
    Ebihara, Y., et al. (2002). Reconstitution of human haematopoiesis in non-obese diabetic/severe combined immunodeficient mice by clonal cells expanded from single CD34+. Br. J. Haematol. 119:525–534.PubMedCrossRefGoogle Scholar
  12. 12.
    Fichelson, S. (1998). The FLT3/FLK2 ligand: structure, functions and prospects. Eur. Cytokine Netw. 9:7–22.PubMedGoogle Scholar
  13. 13.
    Lavagna-Sevenier, C., Marchetto, S., Birnbaum, D. and Rosnet, O. (1998). FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Leukemia 12:301–310.PubMedCrossRefGoogle Scholar
  14. 14.
    Scheijen, B. and Griffin, J.D. (2002). Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene 21:3314–3333.PubMedCrossRefGoogle Scholar
  15. 15.
    Mizuki, M., et al. (2000). Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 96:3907–3914.PubMedGoogle Scholar
  16. 16.
    Kerkhoff, E. and Rapp, U.R. (1998). Cell cycle targets of Ras/Raf signalling. Oncogene 17:1457–1462.PubMedCrossRefGoogle Scholar
  17. 17.
    Reuther, G.W. and Der, C.J. (2000). The Ras branch of small GTPases: Ras family members don’t fall far from the tree. Curr. Opin. Cell Biol. 12:157–165.PubMedCrossRefGoogle Scholar
  18. 18.
    Vivanco, I. and Sawyers, C.L. (2002). The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2:489–501.CrossRefGoogle Scholar
  19. 19.
    Cardone, M.H., et al. (1998). Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang, S., et al. (2000). Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. J. Exp. Med. 192:719–728.PubMedCrossRefGoogle Scholar
  21. 21.
    Rane, S.G. and Reddy, E.P. (2002). JAKs, STATs and Src kinases in hematopoiesis. Oncogene 21:3334–3358.PubMedCrossRefGoogle Scholar
  22. 22.
    Birkenkamp, K.U., Geugien, M., Lemmink, H.H., Kruijer, W. and Vellenga, E. (2001) Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts. Leukemia 15:1923–1931.PubMedGoogle Scholar
  23. 23.
    Marchetto, S., et al. (1999). SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia 13:1374–1382.PubMedCrossRefGoogle Scholar
  24. 24.
    Mizuki, M., et al. (2003). Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood, 101:3164–3173.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen, X.P., et al. (2002). Pim serine/threonine kinases regulate the stability of Socs-1 protein. Proc. Natl. Acad. Sci. USA 99:2175–2180.PubMedCrossRefGoogle Scholar
  26. 26.
    Allen, J.D., Verhoeven, E., Domen, J., van der Valk, M. and Berns, A. (1997). Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc. Oncogene 15:1133–1141.PubMedCrossRefGoogle Scholar
  27. 27.
    Wolf, I. and Rohrschneider, L.R. (1999). Fiz1, a novel zinc finger protein interacting with the receptor tyrosine kinase Flt3. J. Biol. Chem. 274:21,478–21,484.Google Scholar
  28. 28.
    Serve, H., Flesch, K., Serve, S., Fenski, R. and Berdel, W.E. (1999). Expression and function of Flt3/flk2 in human tumor cell lines. Int. J. Oncol. 14:765–770.PubMedGoogle Scholar
  29. 29.
    Drexler, H.G. (1996). Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia 10:588–599.PubMedGoogle Scholar
  30. 30.
    Stacchini, A., et al. (1996). Expression of type III receptor tyrosine kinases FLT3 and KIT and responses to their ligands by acute myeloid leukemia blasts. Leukemia 10:1584–1591.PubMedGoogle Scholar
  31. 31.
    Turner, A.M., Lin, N.L., Issarachai, S., Lyman, S.D. and Broudy, V.C. (1996). FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells. Blood 88:3383–3390.PubMedGoogle Scholar
  32. 32.
    Lisovsky, M., et al. (1996). Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. Blood 88:3987–3997.PubMedGoogle Scholar
  33. 33.
    Nakao, M.J., Janssen, W., Erz, D., Seriu, T. and Bartram C.R. (2000). Tandem duplication of the FLT3 gene in acute lymphoblastic leukemia: a marker for the monitoring of minimal residual disease. Leukemia 14:522–524.PubMedCrossRefGoogle Scholar
  34. 34.
    Yokota, S., et al. (1997). 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 11:1605–1609.PubMedCrossRefGoogle Scholar
  35. 35.
    Horiike, S., et al. (1997). Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia 11:1442–1446.PubMedCrossRefGoogle Scholar
  36. 36.
    Nakao, M., et al. (1996). Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10:1911–1918.PubMedGoogle Scholar
  37. 37.
    Kottaridis, P.D., et al. (2002). 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 100:2393–2398.PubMedCrossRefGoogle Scholar
  38. 38.
    Kiyoi, H., Ohno, R., Ueda, R., Saito, H. and Naoe, T. (2002). Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene 21:2555–2563.PubMedCrossRefGoogle Scholar
  39. 39.
    Hayakawa, F., et al. (2000). Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19:624–631.PubMedCrossRefGoogle Scholar
  40. 40.
    Kiyoi, H., et al. (1998). Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 12:1333–1337.PubMedCrossRefGoogle Scholar
  41. 41.
    Zheng, R., Friedman, A.D. and Small, D. (2002). Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. Blood 100:4154–4161.PubMedCrossRefGoogle Scholar
  42. 42.
    Abu-Duhier, F.M., et al. (2001). Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br. J. Haematol. 113:983–988.PubMedCrossRefGoogle Scholar
  43. 43.
    Thiede, C., et al. (2002). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326–4335.PubMedCrossRefGoogle Scholar
  44. 44.
    Yamamoto, Y., et al. (2001). Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97:2434–2439.PubMedCrossRefGoogle Scholar
  45. 45.
    Griffin, J.D. (2001). Point mutations in the FLT3 gene in AML. Blood 97:2193.CrossRefGoogle Scholar
  46. 46.
    Spiekermann, K., et al. (2002). A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood 100:3423–3425.PubMedCrossRefGoogle Scholar
  47. 47.
    Fenski, R., et al. (2000). Constitutive activation of FLT3 in acute myeloid leukaemia and its consequences for growth of 32D cells. Br. J. Haematol. 108:322–330.PubMedCrossRefGoogle Scholar
  48. 48.
    Kelly, L.M., et al. (2002). FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 99:310–318.PubMedCrossRefGoogle Scholar
  49. 49.
    Kelly, L.M., et al. (2002). PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc. Natl. Acad. Sci. USA 99:8283–8288.PubMedCrossRefGoogle Scholar
  50. 50.
    Kottaridis, P.D., et al. (2001). 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 98:1752–1759.PubMedCrossRefGoogle Scholar
  51. 51.
    Kiyoi, H., et al. (1999). Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93:3074–3080.PubMedGoogle Scholar
  52. 52.
    Kondo, M., et al. (1999). Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med. Pediatr. Oncol. 33:525–529.PubMedCrossRefGoogle Scholar
  53. 53.
    Liang, D.C., et al. (2002). Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia. Cancer 94:3292–3298.PubMedCrossRefGoogle Scholar
  54. 54.
    Meshinchi, S., et al. (2001). Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 97:89–94.PubMedCrossRefGoogle Scholar
  55. 55.
    Schnittger, S., et al. (2002). 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 100:59–66.PubMedCrossRefGoogle Scholar
  56. 56.
    Rowe, J.M. (2000). Treatment of acute myelogenous leukemia in older adults. Leukemia 14:480–487.PubMedCrossRefGoogle Scholar
  57. 57.
    Inokuchi, K., et al. (2002). Loss of DCC gene expression is of prognostic importance in acute myelogenous leukemia. Clin. Cancer Res. 8:1882–1888.PubMedGoogle Scholar
  58. 58.
    Rombouts, W.J., Blokland, I., Lowenberg, B. and Ploemacher, R.E. (2000). Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia 14:675–683.PubMedCrossRefGoogle Scholar
  59. 59.
    Abu-Duhier, F.M., et al. (2000). FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br. J. Haematol. 111:190–195.PubMedCrossRefGoogle Scholar
  60. 60.
    Stirewalt, D.L., et al. (2001). FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97:3589–3595.PubMedCrossRefGoogle Scholar
  61. 61.
    Whitman, S.P., et al. (2001). 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. 61:7233–7239.PubMedGoogle Scholar
  62. 62.
    Boissel, N., et al. (2002). Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy. Leukemia 16:1699–1704.PubMedCrossRefGoogle Scholar
  63. 63.
    Preudhomme, C., et al. (2002). Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 100:2717–2723.PubMedCrossRefGoogle Scholar
  64. 64.
    Iwai, T., et al. (1999). 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 13:38–43.PubMedCrossRefGoogle Scholar
  65. 65.
    Arrigoni, P., et al. (2003). FLT3 internal tandem duplication in childhood acute myeloid leukemia: association with hyperleukocytosis in acute promyelocytic leukemia. Br. J. Haematol. 120:89–92.PubMedCrossRefGoogle Scholar
  66. 66.
    Asou, N., et al. (2001). Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG). Cancer Chemother. Pharmacol. 48(Suppl. 1):S65-S71.PubMedCrossRefGoogle Scholar
  67. 67.
    Hochhaus, A., et al. (2000). Detection and quantification of residual disease in chronic myelogenous leukemia. Leukemia 14:998–1005.PubMedCrossRefGoogle Scholar
  68. 68.
    Serrano, J., et al. (2000). Molecular analysis of lineage-specific chimerism and minimal residual disease by RTPCR of p210(BCR-ABL) and p190(BCR-ABL) after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190(BCR-ABL) detection precede cytogenetic relapse. Blood 95:2659–2665.PubMedGoogle Scholar
  69. 69.
    Stirewalt, D.L., Willman, C.L. and Radich, J.P. (2001). Quantitative, real-time polymerase chain reactions for FLT3 internal tandem duplications are highly sensitive and specific. Leuk. Res. 25:1085–1088.PubMedCrossRefGoogle Scholar
  70. 70.
    Shih, L.Y., et al. (2002). 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 100:2387–2392.PubMedCrossRefGoogle Scholar
  71. 71.
    Hovland, R., Gjertsen, B.T. and Bruserud, O. (2002). Acute myelogenous leukemia with internal tandem duplication of the Flt3 gene appearing or altering at the time of relapse: a report of two cases. Leuk. Lymphoma 43:2027–2029.PubMedCrossRefGoogle Scholar
  72. 72.
    Nakano, Y., et al. (1999). Molecular evolution of acute myeloid leukaemia in relapse: unstable N-ras and FLT3 genes compared with p53 gene. Br. J. Haematol. 104:659–664.PubMedCrossRefGoogle Scholar
  73. 73.
    Gilliland, D.G. (2002). Murky waters for MRD detection in AML: flighty FLT3/ITDs. Blood 100:2277.CrossRefGoogle Scholar
  74. 74.
    Okada, H., et al. (1998). AML1(-/-) embryos do not express certain hematopoiesis-related gene transcripts including those of the PU.1 gene. Oncogene 17:2287–2293.PubMedCrossRefGoogle Scholar
  75. 75.
    Frohling, S., et al. (2002). 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 (AMLSG ULM). Blood 100:4372–4380.PubMedCrossRefGoogle Scholar
  76. 76.
    Sawyers, C.L. (2002). Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell 1:413–415.PubMedCrossRefGoogle Scholar
  77. 77.
    Propper, D.J., et al. (2001). Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J. Clin. Oncol. 19:1485–1492.PubMedGoogle Scholar
  78. 78.
    Weisberg, E., et al. (2002). Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1:433–443.PubMedCrossRefGoogle Scholar
  79. 79.
    Yee, K.W., et al. (2002). SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 100:2941–2949.PubMedCrossRefGoogle Scholar
  80. 80.
    Spiekermann, K., et al. (2003). 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, 101:1494–1504.PubMedCrossRefGoogle Scholar
  81. 81.
    Smolich, B.D., et al. (2001). 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 97:1413–1421.PubMedCrossRefGoogle Scholar
  82. 82.
    Stopeck, A., et al. (2002). Results of a phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. Clin. Cancer Res. 8:2798–2805.PubMedGoogle Scholar
  83. 83.
    Mesters, R.M., et al. (2001). Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood 98:241–243.PubMedCrossRefGoogle Scholar
  84. 84.
    Levis, M., et al. (2002). A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 99:3885–3891.PubMedCrossRefGoogle Scholar
  85. 85.
    Kelly, L.M., et al. (2002). CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 1:421–432.PubMedCrossRefGoogle Scholar
  86. 86.
    Levis, M., Tse, K.F., Smith, B.D., Garrett, E. and Small, D. (2001). A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 98:885–887.PubMedCrossRefGoogle Scholar
  87. 87.
    Teller, S., et al. (2002). Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. Leukemia 16:1528–1534.PubMedCrossRefGoogle Scholar
  88. 88.
    Tse, K.F., et al. (2002). Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia 16:2027–2036.PubMedCrossRefGoogle Scholar
  89. 89.
    Minami, Y., et al. (2002). Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 16:1535–1540.PubMedCrossRefGoogle Scholar
  90. 90.
    Naoe, T., et al. (2001). FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy. Cancer Chemother. Pharmacol. 48(Suppl. 1):S27-S30.PubMedCrossRefGoogle Scholar
  91. 91.
    Zhao, M., et al. (2000). In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 14:374–378.PubMedCrossRefGoogle Scholar
  92. 92.
    Mackarehtschian, K., et al. (1995). Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3:147–161.PubMedCrossRefGoogle Scholar
  93. 93.
    Shaw, S.G., Maung, A.A., Steptoe, R.J., Thomson, A.W. and Vujanovic, N.L. (1998). Expansion of functional NK cells in multiple tissue compartments of mice treated with Flt3-ligand: implications for anti-cancer and anti-viral therapy. J. Immunol. 161:2817–2824.PubMedGoogle Scholar
  94. 94.
    Chen, K., et al. (1997). Antitumor activity and immunotherapeutic properties of Flt3-ligand in a murine breast cancer model. Cancer Res. 57:3511–3516.PubMedGoogle Scholar
  95. 95.
    Lynch, D.H., et al. (1997). Flt3 ligand induces tumor regression and antitumor immune responses in vivo. Nature Med. 3:625–631.PubMedCrossRefGoogle Scholar
  96. 96.
    Wang, A., Braun, S.E., Sonpavde, G. and Cornetta, K. (2000). Antileukemic activity of Flt3 ligand in murine leukemia. Cancer Res. 60:1895–1900.PubMedGoogle Scholar
  97. 97.
    Costello, R.T., et al. (2002). Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99:3661–3667.PubMedCrossRefGoogle Scholar
  98. 98.
    Druker, B.J., et al. (2001). 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. 344:1038–1042.PubMedCrossRefGoogle Scholar
  99. 99.
    Druker, B.J., et al. (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344:1031–1037.PubMedCrossRefGoogle Scholar
  100. 100.
    Voutsadakis, I.A. (2001). The STI571 for the treatment of chronic myelogenous leukemia. Iatriki 80:167–171.Google Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  1. 1.Hematology Division and INSERM U487Institut Gustave-RoussyVillejuifFrance

Personalised recommendations