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Cancer Immunotherapy Targeting WT1 Protein

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Abstract

The Wilms tumor gene WT1 is expressed in leukemias and various kinds of solid tumors, including lung and breast cancer, and exerts an oncogenic function in these malignancies, suggesting that WT1 protein is a novel, overexpressed tumor antigen.The WT1 protein, in fact, is an attractive tumor rejection antigen in animal models. Stimulation in vitro of peripheral blood mononuclear cells with HLA-A*2402- and HLA-A*0201-restricted 9-mer WT1 peptides elicits WT1-specific cytotoxic T-lymphocytes (CTLs), and the CTLs kill endogenously WT1-expressing leukemia or solid tumor cells. Furthermore, WT1 immunoglobulin M (IgM) and IgG antibodies are detected in patients with hematopoietic malignancies such as acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndromes, indicating that WT1 protein overexpressed by leukemia cells is indeed immunogenic.Taken together, these results demonstrate that WT1 protein is a promising tumor antigen for cancer immunotherapy against leukemias and various kinds of solid tumors, including lung and breast cancer.

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References

  1. Call KM, Glaser T, Ito CY, et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms tumor locus.Cell. 1990;60:509–520.

    Article  PubMed  CAS  Google Scholar 

  2. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GAP. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.Nature. 1990;343:774–778.

    Article  PubMed  CAS  Google Scholar 

  3. Gashler AL, Bonthron DT, Madden SL, Rauscher FJI, Collins T, Sukhatme VP. Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1.Proc Natl Acad Sci U S A. 1992;89:10984–10988.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Harrington MA, Konicek B, Song A, Xia X-L, Fredericks WJ, Rauscher FJI. Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms tumor locus.J Biol Chem. 1993;268:21271–21275.

    PubMed  CAS  Google Scholar 

  5. Drummond IA, Madden SL, Rohwer-Nutter P, Bell GI, Sukhatme VP, Rauscher FJI. Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1.Science. 1992;257: 674–678.

    Article  PubMed  CAS  Google Scholar 

  6. Werner H, Re GG, Drummond IA, et al. Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product.Proc Natl Acad Sci U S A. 1993;9:5828–5832.

    Article  Google Scholar 

  7. Englert C, Hou X, Maheswaran S, et al. WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. (EMBO J.) 1995;14:4662–4675.

    CAS  Google Scholar 

  8. Godyer P, Dehbi M,Torban E, Bruening W, Pelletier J. Repression of the retinoic acid receptor-α gene by the Wilms tumor suppressor gene product, wt1.Oncogene. 1995;10:1125–1129.

    Google Scholar 

  9. McCann S, Sullivan J, Guerra J, Arcinas M, Boxer LM. Repression of the c-myb gene by WT1 protein in T and B cell lines.J Biol Chem. 1995;270:23785–23789.

    Article  PubMed  CAS  Google Scholar 

  10. Hewitt SM, Hamada S, McDonnel TJ, Rauscher FJI, Saunders GF. Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms tumor suppressor gene WT1.Cancer Res. 1995;55:5386–5389.

    PubMed  CAS  Google Scholar 

  11. Li RS, Law GL, Seifert RA, Romaniuk PJ, Morris DR. Ornithine decarboxylase is a transcriptional target of tumor suppressor WT1.Exp Cell Res. 1999;247:257–266.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang X, Xing G, Saunders GF. Proto-oncogene N-myc promoter is down regulated by the Wilms’ tumor suppressor gene WT1.AntiCancer Res. 1999;19:1641–1648.

    PubMed  CAS  Google Scholar 

  13. Guan LS, Rauchman M, Wang ZY. Induction of Rb-associated protein (RbAp46) by Wilms’ tumor suppressor WT1 mediates growth inhibition.J Biol Chem. 1998;273:27047–27050.

    Article  PubMed  CAS  Google Scholar 

  14. Kim J, Prawitt D, Bardeesy N, et al. The Wilms’ tumor suppressor gene (WT1) product regulates Dax-1 gene expression during gonadal differentiation.Mol Cell Biol. 1999;19:2289–2299.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Mayo MW, Wang CY, Drouin SS, et al. WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene.EMBO J. 1999;18:3990–4003.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE. Isolation, characterization, and expression of the murine Wilms tumor gene (WT1) during kidney development.Mol Cell Biol. 1991;11: 1707–1712.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Park S, Schalling M, Bernard A, et al. The Wilms tumor gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma.Nature Genet. 1993;4:415–420.

    Article  PubMed  CAS  Google Scholar 

  18. Davies R, Moore A, Schedl A, et al. Multiple roles for the Wilms’ tumor suppressor, WT1.Cancer Res. 1999;59(suppl 7):1747s-1750s [discussion, 1751s].

    PubMed  CAS  Google Scholar 

  19. Moore AW, Mclnnes L, Kreidberg J, Hastie ND, Schedl A. YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis.Development. 1999;126:1845–1857.

    PubMed  CAS  Google Scholar 

  20. Miwa H, Beran M, Aunders GF. Expression of the Wilms tumor gene (WT1) in human leukemias.Leukemia. 1992;6:405–409.

    PubMed  CAS  Google Scholar 

  21. 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.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  23. Bergmann L, Miething C, Maurer U, 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.

    PubMed  CAS  Google Scholar 

  24. Brieger J, Weidmann E, Fenchel K, Mitrou PS, Hoelzer D, Bergmann L. The expression of the Wilms tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells.Leukemia. 1994;8:2138–2143.

    PubMed  CAS  Google Scholar 

  25. Menssen HD, Renkl H-J, Rodeck U, 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.

    PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. Tamaki H, Ogawa H, Ohyashiki K, et al. The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes.Leukemia. 1999;13:393–399.

    Article  PubMed  CAS  Google Scholar 

  28. Shichishima T, Okamoto M, Ikeda K, et al. HLA class II haplotype and quantitation of the WT1 gene in Japanese patients with paroxysmal nocturnal hemoglobinuria (PNH).Blood. In press.

  29. Bruening W, Gros P, Sato T, et al. Analysis of the 11p13 Wilms’ tumor suppressor gene (WT1) in ovarian tumors.Cancer Invest. 1993;11:393–399.

    Article  PubMed  CAS  Google Scholar 

  30. Viel A, Giannini F, Capozzi E, et al. Molecular mechanisms possibly affecting WT1 function in human ovarian tumors.Int J Cancer. 1994;57:515–521.

    Article  PubMed  CAS  Google Scholar 

  31. Campbell CE, Kuriyan NP, Rackley RR, et al. Constitutive expression of the Wilms’ tumor suppressor gene (WT1) in renal cell carcinoma.Int J Cancer. 1998;78:182–188.

    Article  PubMed  CAS  Google Scholar 

  32. Walker C, Rutten F, Yuan X, Pass H, Mew DM, Everitt J. Wilms’ tumor suppressor gene expression in rat and human mesothelioma.Cancer Res. 1994;54:3101–3106.

    PubMed  CAS  Google Scholar 

  33. Amin KM, Litzky LA, Smythe WR, et al. Wilms’ tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesotheliomaAm J Pathol. 1995;146:344–356.

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Langerak AW, Williamson KA, Miyagawa K, Hagemeijer A, Versnel MA, Hastie ND. Expression of the Wilms’ tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin-like growth factor 2 expression.Genes Chromosomes Cancer. 1995;12:87–96.

    Article  PubMed  CAS  Google Scholar 

  35. Rodeck U, Bossler A, Kari C, et al. Expression of the wt1 Wilms’ tumor gene by normal and malignant human melanocytes.Int J Cancer. 1994;59:78–82.

    Article  PubMed  CAS  Google Scholar 

  36. Ladanyi M, Gerald W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor.Cancer Res. 1994;54: 2837–2840.

    PubMed  CAS  Google Scholar 

  37. Silberstein GB,Van Horn K, Strickland P, Roberts CTJ, Daniel CW. Altered expression of the WT1 wilms tumor suppressor gene in human breast cancer.Proc Natl Acad Sci U S A. 1997;94:8132–8137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Loeb DM, Evron E, Patel CB, et al. Wilms’ tumor suppressor gene (WT1) is expressed in primary breast tumors despite tumor-specific promoter methylation.Cancer Res. 2001;61:921–925.

    PubMed  CAS  Google Scholar 

  39. Miyoshi Y, Ando A, Egawa C, et al. High expression of Wilms’ tumor suppressor gene predicts poor prognosis in breast cancer patients.Clin Cancer Res. 2002;8:1167–1171.

    PubMed  CAS  Google Scholar 

  40. Oji Y, Ogawa H, Tamaki H, et al. Expression of the Wilms’ tumor gene WT1 in solid tumors and its involvement in tumor cell growth.Jpn J Cancer Res. 1999;90:194–204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Menssen HD, Bertelmann E, Bartelt S, et al. Wilms’ tumor gene (WT1) expression in lung cancer, colon cancer and glioblastoma cell lines compared to freshly isolated tumor specimens.J Cancer Res Clin Oncol. 2000;126:226–332.

    Article  PubMed  CAS  Google Scholar 

  42. Oji Y, Miyoshi, S, Maeda H, et al. Overexpression of the Wilms’ tumor gene WT1 inde novo lung cancers.Int J Cancer. In press.

  43. Coppes MJ, Campbell CE, Williams BRG. The role of WT1 in Wilms tumorigenesis.FASEB J. 1993;7:886–895.

    Article  PubMed  CAS  Google Scholar 

  44. Rauscher FJI. The WT1 Wilms tumor gene product: a develop- mentally regulated transcription factor in the kidney that functions as a tumor suppressor.FASEB J. 1993;7:896–903.

    Article  PubMed  CAS  Google Scholar 

  45. Haber DA, Park S, Maheswaran S, et al. WT1-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant.Science. 1993;262:2057–2059.

    Article  PubMed  CAS  Google Scholar 

  46. Algar EM, Kenney MT, Simms LA, Smith SI, Kida Y, Smith PJ. Homozygous intragenic deletion in the WT1 gene in a sporadic Wilms’ tumour associated with high levels of expression of a truncated transcript.Hum Mutat. 1995;5:221–227.

    Article  PubMed  CAS  Google Scholar 

  47. Little M, Wells C. A clinical overview of WT1 gene mutations.Hum Mutat. 1997;9:209–225.

    Article  PubMed  CAS  Google Scholar 

  48. Sugiyama H. Wilms’ tumor gene WT1: its oncogenic function and clinical application.Int J Hematol. 2001;73:177–187.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  50. Yamagami T, Sugiyama H, Inoue K, et al. Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis.Blood. 1996;87:2878–2884.

    PubMed  CAS  Google Scholar 

  51. Inoue K, Tamaki H, Ogawa H, et al. Wilms’ tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells.Blood. 1998;91:2969–2976.

    PubMed  CAS  Google Scholar 

  52. Tsuboi A, Oka Y, Ogawa H, 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).Leuk Res. 1999;23: 499–505.

    Article  PubMed  CAS  Google Scholar 

  53. Osaka M, Koami K, Sugiyama T. WT1 contributes to leukemogen- esis: expression patterns in 7, 12-dimthylbenz[a]anthracence (DMBA)-induced leukemia.Int J Cancer. 1997;72:696–699.

    Article  PubMed  CAS  Google Scholar 

  54. Oka Y, Tsuboi A, Elisseeva OA, Udaka K, Sugiyama H. WT1 as a novel target antigen for cancer immunotherapy.Curr Cancer Drug Targets. 2001;2:45–54.

    Article  Google Scholar 

  55. Oka Y, Udaka K, Tsuboi A, et al. Cancer immunotherapy targeting Wilms tumor gene WT1 product.J Immunol. 2000;164: 1873–1880.

    Article  PubMed  CAS  Google Scholar 

  56. Tsuboi A, Oka Y, Ogawa H, et al. Cytotoxic T-lymphocyte responses elicited to Wilms’ tumor gene WT1 product by DNA vaccination.J Clin Immunol. 2000;20:195–202.

    Article  PubMed  CAS  Google Scholar 

  57. 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.

    PubMed  CAS  Google Scholar 

  58. Oka Y, Elisseeva OA, Tsuboi A, et al. Human cytotoxic T lymphocyte responses specific for peptides of wild-type Wilms tumor gene WT1 product.Immunogenetics. 2000;51:99–107.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  60. Yasukawa M. Immunotherapy for leukemia targeting the Wilms’ tumor gene.Leuk Lymph. 2001;42:267–273.

    Article  CAS  Google Scholar 

  61. 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.

    PubMed  CAS  Google Scholar 

  62. 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.

    Article  PubMed  CAS  Google Scholar 

  63. Elisseeva OA, Oka Y, Tsuboi A, et al. Humoral immune responses against Wilms’ tumor gene WT1 product in patients with hemato- poietic malignancies.Blood. 2002;99:3272–3279.

    Article  PubMed  CAS  Google Scholar 

  64. Gaiger A, Carter L, Greinix H, et al. WT1-specific serum antibodies in patients with leukemia.Clin Cancer Res. 2001;7:761s-765s.

    PubMed  CAS  Google Scholar 

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Correspondence to Haruo Sugiyama.

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Sugiyama, H. Cancer Immunotherapy Targeting WT1 Protein. Int J Hematol 76, 127–132 (2002). https://doi.org/10.1007/BF02982574

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