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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies

Leukemia volume 17, pages 1301–1312 (2003)Cite this article

Abstract

Among clinicians, initial awareness of the Wilms' tumor gene was limited mostly to pediatric oncologists. Almost a decade ago, overexpression of Wilms' tumor 1 (WT1) was observed in adult acute leukemia. Subsequent studies indicated that WT1 overexpression occurs in most cases of acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS). Limited tissue expression of WT1 in adults suggests that WT1 can be a target for leukemia/MDS therapy. WT1 expression in stem/progenitor cells remains unsettled. However, lack of progenitor cell suppression by WT1 antisense or WT1-specific cytotoxic T cells provide some assurance that WT1 expression in progenitor cells is minimal or absent. Immunotherapy-based WT1 approaches are furthest along in preclinical development. WT1-specific cytotoxic lymphocytes can be generated from normals and leukemic patients. In mice, WT1 vaccines elicit specific immune responses without evidence of tissue damage. In this paper, we review studies validating the immunogenicity of WT1 and propose that leukemia and MDS may be a good clinical model to test the efficacy of a WT1 vaccine.

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References

  1. Baudard M, Beauchamp-Nicoud A, Delmer A, Rio B, Blanc C, Zittoun R et al. Has the prognosis of adult patients with acute myeloid leukemia improved over years? A single institution experience of 784 consecutive patients over a 16-year period. Leukemia 1999; 13: 1481–1490.

    CAS  PubMed  Google Scholar 

  2. Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet 1998; 351: 700–708.

    Article  CAS  PubMed  Google Scholar 

  3. Heaney ML, Golde DW . Myelodysplasia. N Engl J Med 1999; 340: 1649–1660.

    CAS  PubMed  Google Scholar 

  4. Pui CH, Evans WE . Acute lymphoblastic leukemia. N Engl J Med 1998; 339: 605–615.

    CAS  PubMed  Google Scholar 

  5. Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.

    PubMed  Google Scholar 

  6. Guglielmi C, Arcese W, Dazzi F, Brand R, Bunjes D, Verdonck LF et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood 2002; 100: 397–405.

    CAS  PubMed  Google Scholar 

  7. Falkenburg JH, Wafelman AR, Joosten P, Smit WM, van Bergen CA, Bongaerts R et al. Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. Blood 1999; 94: 1201–1208.

    CAS  PubMed  Google Scholar 

  8. Foon KA, Smalley RV, Riggs CW, Gale RP . The role of immunotherapy in acute myelogenous leukemia. Arch Intern Med 1983; 143: 1726–1731.

    CAS  PubMed  Google Scholar 

  9. Arceci RJ . The potential for antitumor vaccination in acute myelogenous leukemia. J Mol Med 1998; 76: 80–93.

    CAS  PubMed  Google Scholar 

  10. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J et al. The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 2000; 13: 193–207.

    CAS  PubMed  Google Scholar 

  11. Scharnhorst V, van der Eb AJ, Jochemsen AG . WT1 proteins: functions in growth and differentiation. Gene 2001; 273: 141–161.

    CAS  PubMed  Google Scholar 

  12. Silberstein GB, Van Horn K, Strickland P, Roberts Jr CT, Daniel CW . Altered expression of the WT1 Wilms' tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA 1997; 94: 8132–8137.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990; 60: 509–520.

    CAS  PubMed  Google Scholar 

  14. Miwa H, Beran M, Saunders GF . Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 1992; 6: 405–940.

    CAS  PubMed  Google Scholar 

  15. Miyagi T, Ahuja H, Kubota T, Kubonishi I, Koeffler HP, Miyoshi I . Expression of the candidate Wilms' tumor gene, WT1, in human leukemia cells. Leukemia 1993; 7: 970–977.

    CAS  PubMed  Google Scholar 

  16. Fukahori S . Quantification of WT1 mRNA by competitive NASBA in AML patients. Kurume Med J 2001; 48: 129–134.

    CAS  PubMed  Google Scholar 

  17. Kreuzer K, Saborowski A, Lupberger J, Appelt C, Na I, Coutre P et al. Fluorescent 5'-exonuclease assay for the absolute quantification of Wilms' tumour gene (WT1) mRNA: implications for monitoring human disease. Br J Haematol 2001; 114: 313–318.

    CAS  PubMed  Google Scholar 

  18. Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–3079.

    CAS  PubMed  Google Scholar 

  19. Patmasiriwat P, Fraizer GC, Claxton D, Kantarjian H, Saunders GF . Expression pattern of WT1 and GATA-1 in AML with chromosome 16q22 abnormalities. Leukemia 1996; 10: 1127–1133.

    CAS  PubMed  Google Scholar 

  20. Schmid D, Heinze G, Linnerth B, Tisljar K, Kusec R, Geissler K et al. Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia. Leukemia. 1997; 11: 639–643.

    CAS  PubMed  Google Scholar 

  21. Karakas T, Miething CC, Maurer U, Weidmann E, Ackermann H, Hoelzer D et al. The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia. Leukemia 2002; 16: 846–854.

    CAS  PubMed  Google Scholar 

  22. Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E et al. High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 1997; 90: 1217–1225.

    CAS  PubMed  Google Scholar 

  23. Algar E, Blackburn D, Kromykh T, Taylor G, Smith P . Mutation analysis of the WT1 gene in sporadic childhood leukaemia. Leukemia 1997; 11: 110–113.

    CAS  PubMed  Google Scholar 

  24. Niegemann E, Wehner S, Kornhuber B, Schwabe D, Ebener U . wt1 gene expression in childhood leukemias. Acta Haematol 1999; 102: 72–76.

    CAS  PubMed  Google Scholar 

  25. Ozgen U, Anak S, Ozbek U, Sarper N, Eryilmaz E, Agaoglu L et al. wt1 gene expression in childhood acute leukemias. Acta Haematol 2000; 103: 229–302.

    CAS  PubMed  Google Scholar 

  26. Trka J, Kalinova M, Hrusak O, Zuna J, Krejci O, Madzo J et al. Real-time quantitative PCR detection of WT1 gene expression in children with AML: prognostic significance, correlation with disease status and residual disease detection by flow cytometry. Leukemia 2002; 16: 1381–1389.

    CAS  PubMed  Google Scholar 

  27. Gaiger A, Linnerth B, Mann G, Schmid D, Heinze G, Tisljar K et al. Wilms' tumour gene (wt1) expression at diagnosis has no prognostic relevance in childhood acute lymphoblastic leukaemia treated by an intensive chemotherapy protocol. Eur J Haematol 1999; 63:86–93.

    CAS  PubMed  Google Scholar 

  28. Menssen HD, Renkl HJ, Rodeck U, Maurer J, Notter M, Schwartz S et al. Presence of Wilms' tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia 1995; 9: 1060–1067.

    CAS  PubMed  Google Scholar 

  29. Carapeti M, Goldman JM, Cross NC . Dominant-negative mutations of the Wilms' tumour predisposing gene (WT1) are infrequent in CML blast crisis and de novo acute leukaemia. Eur J Haematol 1997; 58: 346–349.

    CAS  PubMed  Google Scholar 

  30. Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 2002; 16: 2115–2121.

    CAS  PubMed  Google Scholar 

  31. Im HJ, Kong G, Lee H . Expression of Wilms tumor gene (WT1) in children with acute leukemia. Pediatr Hematol Oncol 1999; 16: 109–118.

    CAS  PubMed  Google Scholar 

  32. Inoue K, Ogawa H, Sonoda Y, Kimura T, Sakabe H, Oka Y et al. Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 1997; 89: 1405–1412.

    CAS  PubMed  Google Scholar 

  33. Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M et al. Growth inhibition of human leukemic cells by WT1 (Wilms Tumor Gene) antisense oligonucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 1996; 87: 2878–2884.

    CAS  PubMed  Google Scholar 

  34. Inoue K, Ogawa H, Yamagami T, Soma T, Tani Y, Tatekawa T et al. Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood 1996; 88: 2267–2278.

    CAS  PubMed  Google Scholar 

  35. Gaiger A, Schmid D, Heinze G, Linnerth B, Greinix H, Kalhs P et al. Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia 1998; 12: 1886–1894.

    CAS  PubMed  Google Scholar 

  36. King-Underwood L, Pritchard-Jones K . Wilms' tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 1998; 91: 2961–2968.

    CAS  PubMed  Google Scholar 

  37. Miyagawa K, Hayashi Y, Fukuda T, Mitani K, Hirai H, Kamiya K . Mutations of the WT1 gene in childhood nonlymphoid hematological malignancies. Genes Chromosomes Cancer 1999; 25: 176–183.

    CAS  PubMed  Google Scholar 

  38. Tamaki H, Ogawa H, Ohyashiki K, Ohyashiki JH, Iwama H, Inoue K et al. The Wilms' tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 2000; 13: 393–399.

    Google Scholar 

  39. Patmasiriwat P, Fraizer G, Kantarjian H, Saunders GF . WT1 and GATA1 expression in myelodysplastic syndrome and acute leukemia. Leukemia 1999; 13: 891–900.

    CAS  PubMed  Google Scholar 

  40. Rosse WF . New insights into paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol 2001; 8: 61–67.

    CAS  PubMed  Google Scholar 

  41. Shichishima T, Okamoto M, Ikeda K, Kaneshige T, Sugiyama H, Terasawa T et al. HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood 2002; 100: 22–28.

    CAS  PubMed  Google Scholar 

  42. Hosoya N, Miyagawa K, Mitani K, Yazaki Y, Hirai H . Mutation analysis of the WT1 gene in myelodysplastic syndromes. Jpn J Cancer Res 1998; 89: 821–824.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Mori N, Okada M, Motoji T, Mizoguchi H . Mutation of the WT1 gene in myelodysplastic syndrome and acute myeloid leukemia post myelodysplastic syndrome. Br J Haematol 1999; 105: 844–845.

    CAS  PubMed  Google Scholar 

  44. Takahashi T, Yamamoto R, Tanaka K, Kamada N, Miyagawa K . Mutation analysis of the WT1 gene in secondary leukemia. Leukemia 2000; 14: 1316–1317.

    CAS  PubMed  Google Scholar 

  45. Fraizer G, Patmasiriwat P, Zhang X, Saunders GF . Expression of the tumor suppressor gene WT1 in both human and mouse bone marrow. Blood 1995; 86: 4704–4706.

    CAS  PubMed  Google Scholar 

  46. Brieger J, Weidmann E, Maurer U, Hoelzer D, Mitrou PS, Bergmann L . The Wilms' tumor gene is frequently expressed in acute myeloblastic leukemias and may provide a marker for residual blast cells detectable by PCR. Ann Oncol 1995; 6: 811–816.

    CAS  PubMed  Google Scholar 

  47. Maurer U, Weidmann E, Karakas T, Hoelzer D, Bergmann L . Wilms tumor gene (wt1) mRNA is equally expressed in blast cells from acute myeloid leukemia and normal CD34+ progenitors. Blood 1997; 90: 4230–4231.

    CAS  PubMed  Google Scholar 

  48. Baird PN, Simmons PJ . Expression of Wilms' tumor gene (WT1) in normal hemopoiesis. Exp Hematol 1997; 25:312–320.

    CAS  PubMed  Google Scholar 

  49. Menssen HD, Renkl HJ, Rodeck U, Kari C, Schwartz S, Thiel E . Detection by monoclonal antibodies of the Wilms' tumor (WT1) nuclear protein in patients with acute leukemia. Int J Cancer 1997; 70: 518–523.

    CAS  PubMed  Google Scholar 

  50. Gaiger A, Reese V, Disis ML, Cheever MA . Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood 2000; 96: 1480–1489.

    CAS  PubMed  Google Scholar 

  51. Hosen N, Sonoda Y, Oji Y, Kimura T, Minamiguchi H, Tamaki H et al. Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells. Br J Haematol 2002; 116: 409–420.

    CAS  PubMed  Google Scholar 

  52. King-Underwood L, Pritchard-Jones K . Mutations in the Wilms' tumor gene WT1 in leukemias. Blood 1996; 87: 2171–2179.

    CAS  PubMed  Google Scholar 

  53. Menssen HD, Renkl HJ, Entezami M, Thiel E . Wilms' tumor gene expression in human CD34+ hematopoietic progenitors during fetal development and early clonogenic growth. Blood 1997; 89: 3486–3487.

    CAS  PubMed  Google Scholar 

  54. Maurer U, Brieger J, Weidmann E, Mitrou PS, Hoelzer D, Bergmann L . The Wilms' tumor gene is expressed in a subset of CD34+ progenitors and downregulated early in the course of differentiation in vitro. Exp Hematol 1997; 25: 945–950.

    CAS  PubMed  Google Scholar 

  55. Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Tamaki H, Oji Y et al. Constitutive expression of the Wilms' tumor gene WT1 inhibits the differentiation of myeloid progenitor cells but promotes their proliferation in response to granulocyte-colony stimulating factor (G-CSF). Leukemia Res 1999; 23: 499–505.

    CAS  Google Scholar 

  56. Svedberg H, Richter J, Gullberg U . Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34(+) progenitor cells. Leukemia 2001; 15: 1914–1922.

    CAS  PubMed  Google Scholar 

  57. Ellisen LW, Carlesso N, Cheng T, Scadden DT, Haber DA . The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. EMBO J 2001; 20: 1897–1909.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ohminami H, Yasukawa M, Fujita S . HLA class I-restricted lysis of leukemia cells by a CD8+ cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood 2000; 95: 286–293.

    CAS  PubMed  Google Scholar 

  59. Gao L, Bellantuono I, Elsässer A, Marley SB, Gordon MY, Goldman JM et al. Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 2000; 95: 2198–2203.

    CAS  PubMed  Google Scholar 

  60. Zanjani ED, Almeida-Porada G, Livingston AG, Flake AW, Ogawa M . Human bone marrow CD34− cells engraft in vivo and undergo multilineage expression that includes giving rise to CD34+ cells. Exp Hematol 1998; 26: 353–360.

    CAS  PubMed  Google Scholar 

  61. Menke AL, van der Eb AJ, Jochemsen AG . The Wilms' tumor 1 gene: oncogene or tumor suppressor gene? Int Rev Cytol 1998; 181: 151–212.

    CAS  PubMed  Google Scholar 

  62. Algar EM, Khromykh T, Smith SI, Blackburn DM, Bryson GJ, Smith PJ . A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines. Oncogene 1996; 12: 1005–1014.

    CAS  PubMed  Google Scholar 

  63. Murata Y, Kudoh T, Sugiyama H, Toyoshima K, Akiyama T . The Wilms tumor suppressor gene WT1 induces G1 arrest and apoptosis in myeloblastic leukemia M1 cells. FEBS Lett 1997; 409: 41–45.

    CAS  PubMed  Google Scholar 

  64. Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T et al. Wilms' tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 1998; 91: 2969–2976.

    CAS  PubMed  Google Scholar 

  65. Greiner J, Ringhoffer M, Simikopinko O, Szmaragowska A, Huebsch S, Maurer U et al. Simultaneous expression of different immunogenic antigens in acute myeloid leukemia. Exp Hematol 2000; 28: 1413–1422.

    CAS  PubMed  Google Scholar 

  66. Svedberg H, Chylicki K, Baldetorp B, Rauscher FJ, Gullberg U . Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program. Oncogene 1998; 16: 925–932.

    CAS  PubMed  Google Scholar 

  67. Sekiya M, Adachi M, Hinoda Y, Imai K, Yachi A . Downregulation of Wilms' tumor gene (wt1) during myelomonocytic differentiation in HL60 cells. Blood 1994; 83: 1876–1882.

    CAS  PubMed  Google Scholar 

  68. Svedberg H, Chylicki K, Gullberg U . Downregulation of Wilms' tumor gene (WT1) is not a prerequisite for erythroid or megakaryocytic differentiation of the leukemic cell line K562. Exp Hematol 1999; 27: 1057–1062.

    CAS  PubMed  Google Scholar 

  69. Phelan SA, Lindberg C, Call KM . Wilms' tumor gene, WT1, mRNA is down-regulated during induction of erythroid and megakaryocytic differentiation of K562 cells. Cell Growth Differ 1994; 5: 677–686.

    CAS  PubMed  Google Scholar 

  70. Carrington D, Algar E . Overexpression of murine WT1 +/+ and −/− isoforms has no effect on chemoresistance but delays differentiation in the K562 cell line. Leukemia Res 2000; 24: 927–936.

    CAS  Google Scholar 

  71. Smith SI, Well D, Johnson GR, Boyd AW, Li CL . Expression of the Wilms' tumor suppressor gene, WT1, is unregulated by leukemia inhibitory factor and induces monocytic differentiation in M1 leukemia cells. Blood 1998; 91: 764–773.

    CAS  PubMed  Google Scholar 

  72. Smith SI, Down M, Boyd AW, Li CL . Expression of the Wilms' tumor suppressor gene, WT1, reduces the tumorigenicity of the leukemia cell line M1 in C.B-17 scid/scid mice. Cancer Res 2000; 60: 808–814.

    CAS  PubMed  Google Scholar 

  73. Murata Y, Kudoh T, Sugiyama H, Toyoshima K, Akiyama T . The Wilms tumor suppressor gene WT1 induces G1 arrest and apoptosis in myeloblastic leukemia M1 cells. FEBS Lett 1997; 409: 41–45.

    CAS  PubMed  Google Scholar 

  74. Yamagami T, Ogawa H, Tamaki H, Oji Y, Soma T, Oka Y et al. Suppression of Wilms' tumor gene (WT1) expression induces G2/M arrest in leukemic cells. Leukamia Res 1999; 22: 383–384.

    Google Scholar 

  75. Hubinger G, Schmid M, Linortner S, Manegold A, Bergmann L, Maurer U . Ribozyme-mediated cleavage of wt1 transcripts suppresses growth of leukemia cells. Exp Hematol 2001; 29: 1226–1235.

    CAS  PubMed  Google Scholar 

  76. Hirose M, Kuroda Y . p53 may mediate the mdr-1 expression via the WT1 gene in human vincristine-resistant leukemia/lymphoma cell lines. Cancer Lett 1998; 129: 165–171.

    CAS  PubMed  Google Scholar 

  77. Ringden O, Labopin M, Gorin NC, Schmitz N, Schaefer UW, Prentice HG et al. Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia? Br J Haematol 2000; 111: 1130–1137.

    CAS  PubMed  Google Scholar 

  78. Fowler DH, Gress RE . Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma. Leukemia Lymphoma 2000; 38: 221–234.

    CAS  PubMed  Google Scholar 

  79. Bonnet D, Warren EH, Greenberg PD, Dick JE, Riddell SR . CD8+ minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia stem cells. Proc Natl Acad Sci USA 1999; 96: 8639–8644.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Simpson E . Minor transplantation antigens. Transplantation 1998; 65: 611–616.

    CAS  PubMed  Google Scholar 

  81. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E . Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. Blood 1999; 93: 2336–2341.

    CAS  PubMed  Google Scholar 

  82. Goulmy E . Alloimmune T cells for adoptive therapy of hematological malignancies. In: Schechter GP, Berliner N, Telen MJ, Bajus JL (eds). Hematology 2000, The American Society of Hematology Education Program Book, American Society of Hematology: Washington DC, pp 366–370.

  83. Molldrem J, Dermine S, Parker K, Jiang YZ, Mavroudis D, Hensel N et al. Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood 1996; 88: 2450–2457.

    CAS  PubMed  Google Scholar 

  84. Dolstra H, Fredrix H, Maas F, Coulie PG, Brasseur F, Mensick E et al. A human minor histocompatibility antigen specific for B cell acute lymphoblastic leukemia. J Exp Med 1999; 189: 301–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Molldrem JJ, Lee PP, Wang C, Felio K, Kantarjian HM, Champlin RE et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 2000; 6: 1018–1023.

    CAS  PubMed  Google Scholar 

  86. Oka Y, Elisseeva OA, Tsuboi A, Udaka K, Ogawa H, Li H et al. Human cytotoxic T-lumphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1) product. Immunogenetics 2000; 51: 99–107.

    CAS  PubMed  Google Scholar 

  87. Azuma T, Makita M, Ninomiya K, Fujita S, Harada M, Yasukawa M . Identification of a novel WT1-derived peptide which induces human leucocyte antigen-A24-restricted anti-leukaemia cytotoxic T lymphocytes. Br J Haematol 2002; 116: 601–603.

    CAS  PubMed  Google Scholar 

  88. Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K et al. Cancer immunotherapy targeting Wilms' tumor gene WT1 product. J Immunol 2000; 164: 1873–1880.

    CAS  PubMed  Google Scholar 

  89. Disis ML, Calenoff E, McLaughlin G, Murphy AE, Chen W, Groner B et al. Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 1994; 54: 16–20.

    CAS  PubMed  Google Scholar 

  90. Lubin R, Schlichtholz B, Teillaud JL, Garay E, Bussel A, Wild CP . p53 antibodies in patients with various types of cancer: assay, identification, and characterization. Clin Cancer Res 1995; 1: 1463–1469.

    CAS  PubMed  Google Scholar 

  91. Gaiger A, Carter L, Greinix H, Carter D, McNeill PD, Houghton RL et al. WT1-specific serum antibodies in patients with leukemia. Clin Cancer Res. 2001; 7(Suppl): 761s–765s.

    CAS  PubMed  Google Scholar 

  92. Elisseeva OA, Oka Y, Tsuboi A, Ogata K, Wu F, Kim EH et al. Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. Blood 2002; 99: 3272–3279.

    CAS  PubMed  Google Scholar 

  93. Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE . Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci USA 1991; 88: 9618–9622.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Rauscher III FJ, Morris JF, Tournay OE, Cook DM, Curran T . Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. Science 1990; 30: 1259–1262.

    Google Scholar 

  95. Madden SL, Cook DM, Morris JF, Gashler A, Sukhatme VP, Rauscher III FJ . Transcriptional repression mediated by the WT1 Wilms tumor gene product. Science 1991; 253: 1550–1553.

    CAS  PubMed  Google Scholar 

  96. Van Dijk JP, Knops GH, Van De Locht LT, Menke AL, Jansen JH, Mensink EJ et al. Abnormal WT1 expression in the CD34-negative compartment in myelodysplastic bone marrow. Br J Haematol 2002; 118: 1027–1033.

    CAS  PubMed  Google Scholar 

  97. Disis ML, Cheever MA . Oncogenic proteins as tumor antigens. In: Alt F, Marrack P (eds). Current Opinion in Immunology, Vol. 5. London U.K: Current biology Ltd., 1996, pp 637–642.

    Google Scholar 

  98. Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Li H, Kawasaki K et al. Cytotoxic T-lymphocyte responses elicited to Wilms' tumor gene WT1 product by DNA vaccination. J Clin Immunol 2000; 20: 195–202.

    CAS  PubMed  Google Scholar 

  99. Kwon ED, Hurwitz AA, Foster BA, Madias C, Feldhaus AL, Greenberg NM et al. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA 1997; 94: 8099–8103.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Tanghe A, D'Souza S, Rosseels V, Denis O, Ottenhoff TH, Dalemans W et al. Improved immunogenicity and protective efficacy of a tuberculosis DNA vaccine encoding Ag85 by protein boosting. Infect Immunol 2001; 69: 3041–3047.

    CAS  Google Scholar 

  101. Surman S, Lockey TD, Slobod KS, Jones B, Riberdy M, White SW et al. Localization of CD4+ T cell epitope hotspots to exposed strands of HIV envelope glycoprotein suggests structural influences on antigen processing. Proc Natl Acad Sci USA 2001; 98: 4587–4592.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Amara RR, Villinger F, Altman JD, Lydy SL, O'Neil SP, Staprans SI et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 2001; 292: 69–74.

    CAS  PubMed  Google Scholar 

  103. Pancholi P, Lee DH, Liu Q, Tackney C, Taylor P, Perkus M et al. DNA prime/canarypox boost-based immunotherapy of chronic hepatitis B virus infection in a chimpanzee. Hepatology 2001; 33: 448–454.

    CAS  PubMed  Google Scholar 

  104. Bonnet MC, Tartaglia J, Verdier F, Kourilsky P, Lindberg A, Klein M et al. Recombinant viruses as a tool for therapeutic vaccination against human cancers. Immunol Lett 2000; 74: 11–25.

    CAS  PubMed  Google Scholar 

  105. Ramshaw IA, Ramsay AJ . The prime-boost strategy: exciting prospects for improved vaccination. Immunol Today 2000; 21: 163–165.

    CAS  PubMed  Google Scholar 

  106. Foster MR, Johnson JE, Olson SJ, Allred C . Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas. Arch Pathol Lab Med 2001; 125: 1316–1320.

    CAS  PubMed  Google Scholar 

  107. Silberstein GB, Van Horn K, Strickland P, Roberts Jr CT, Daniel CW . Altered expression of the WT1 Wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA 1997; 94: 8132–8137.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Loeb DM, Evron E, Patel CB, Sharma PM, Niranjan B, Buluwela L et al. Wilms' tumor suppressor gene (WT1) is expressed in primary breast tumors despite tumor-specific promoter methylation. Cancer Res 2001; 61: 921–925.

    CAS  PubMed  Google Scholar 

  109. Miyoshi Y, Ando A, Egawa C, Taguchi T, Tamaki Y et al. High expression of Wilms' tumor suppressor gene predicts poor prognosis in breast cancer patients. Clin Cancer Res 2002; 8: 1167–1171.

    CAS  PubMed  Google Scholar 

  110. Bruening W, Gros P, Sato T, Stanimir J, Nakamura Y, Housman D et al. Analysis of the 11p13 Wilms' tumor suppressor gene (WT1) in ovarian tumors. Cancer Invest 1993; 11: 393–399.

    CAS  PubMed  Google Scholar 

  111. Goldstein NS, Bassi D, Uzieblo A . WT1 is an integral compo-nent of an antibody panel to distinguish pancreaticobiliary and some ovarian epithelial neoplasms. Am J Clin Pathol 2001; 116: 246–252.

    CAS  PubMed  Google Scholar 

  112. Rodeck U, Bossler A, Kari C, Humphreys CW, Gyorfi T, Maurer J et al. Expression of the wt1 Wilms' tumor gene by normal and malignant human melanocytes. Int J Cancer 1994; 59: 78–82.

    CAS  PubMed  Google Scholar 

  113. Nonomura N, Imazu T, Harada Y, Nozawa M, Ono Y, Fukui T et al. Molecular staging of testicular cancer using polymerase chain reaction of the testicular cancer-specific genes. Hinyokika Kiyo 1999; 45: 593–597.

    CAS  PubMed  Google Scholar 

  114. Lion T, Henn T, Gaiger A, Kalhs P, Gadner H . Early detection of relapse after bone marrow transplantation in patients with chronic myelogenous leukaemia. Lancet 1993; 341: 275–276.

    CAS  PubMed  Google Scholar 

  115. Gaiger A, Henn T, Horth E, Geissler K, Mitterbauer G, Maier-Dobersberger T et al. Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. Blood 1995; 86: 2371–2378.

    CAS  PubMed  Google Scholar 

  116. Lion T, Gaiger A, Henn T, Horth E, Haas OA, Geissler K et al. Use of quantitative polymerase chain reaction to monitor residual disease in chronic myelogenous leukemia during treatment with interferon. Leukemia. 1995; 9: 1353–1360.

    CAS  PubMed  Google Scholar 

  117. Stock W, Westbrook CA, Peterson B, Arthur DC, Szatrowski TP, Silver RT et al. Value of molecular monitoring during the treatment of chronic myeloid leukemia: A Cancer and Leukemia Group B study. J Clin Oncol 1997; 15: 26–36.

    CAS  PubMed  Google Scholar 

  118. Kreuzer KA, Lass U, Nagel S, Ellerbrok H, Pauli G, Pawlaczyk-Peter B et al. Applicability of an absolute quantitative procedure to monitor intra-individual bcr/abl transcript kinetics in clinical samples from chronic myelogenous leukemia patients. Int J Cancer 2000; 86: 741–746.

    CAS  PubMed  Google Scholar 

  119. Olavarria E, Kanfer E, Szydlo R, Kaeda J, Rezvani K, Cwynarski K et al. Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2001; 97: 1560–1565.

    CAS  PubMed  Google Scholar 

  120. Greenberg PL . Biologic and clinical implications of marrow culture studies in the myelodysplastic syndromes. Semin Hematol 1996; 33: 163–175.

    CAS  PubMed  Google Scholar 

  121. Nilsson L, Astrand-Grundstrom I, Anderson K, Arvidsson I, Hokland P, Bryder D et al. Involvement and functional impairment of the CD34(+)CD38(−)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8. Blood 2002; 100: 259–267.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Dallas, TX, USA

    C Rosenfeld

  2. Corixa Corporation, Seattle, WA, USA

    M A Cheever

  3. University of Vienna, Vienna, Austria

    A Gaiger

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  1. C Rosenfeld
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  2. M A Cheever
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Rosenfeld, C., Cheever, M. & Gaiger, A. WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies. Leukemia 17, 1301–1312 (2003). https://doi.org/10.1038/sj.leu.2402988

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