International Journal of Hematology

, Volume 76, Issue 2, pp 117–126 | Cite as

The Role of WT1 in Oncogenesis: Tumor Suppressor or Oncogene?

  • David M. Loeb
  • Saraswati Sukumar
Progress in hematology

Abstract

Although originally identified as a tumor suppressor gene, WT1 is overexpressed in a variety of hematologic malignancies and solid tumors, including acute leukemia, breast cancer, malignant mesothelioma, renal cell carcinoma, and others. Overex-pression of both wild-type and mutant WT1 has been reported. In some cases, this finding represents overexpression of a gene that should be expressed at lower levels, but in other cases, WT1 is expressed at high levels in a tissue type in which there is normally no expression at all. In this review, the mechanisms of altered WT1 expression are explored, including changes in promoter methylation. WT1 target genes that may be important for oncogenesis are discussed, as is the use of WT1 expression as a diagnostic tool. The prognostic implications of altered WT1 expression and the potential for immunotherapy aimed at WT1 are also discussed.

Key words

Leukemia Wilms’ tumor Breast cancer Mesothelioma Transcription factor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 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.Google Scholar
  2. 2.
    Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GAP. Homozygous deletion in Wilms’ tumor of a zinc-finger gene identified by chromosome jumping.Nature. 1990;343:774–778.Google Scholar
  3. 3.
    Haber DA, Sohn RL, Buckler AJ, et al. Alternative splicing and genomic structure of the Wilms tumor gene WT1.Proc Natl Acad Sci U S A. 1991;88:9618–9622.Google Scholar
  4. 4.
    Sharma PM, Bowman M, Madden SL, Rauscher FJ 3rd, Sukumar S. RNA editing in the Wilms’ tumor susceptibility gene, WT1.Genes Dev. 1994;8:720–731.Google Scholar
  5. 5.
    Bruening W, Pelletier J. A non-AUG translational initiation event generates novel WT1 isoforms.J Biol Chem. 1996;271:8646–8654.Google Scholar
  6. 6.
    Scharnhorst V, Dekker P, van der Eb AJ, Jochemsen AG. Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties.J Biol Chem. 1999;274:23456–23462.Google Scholar
  7. 7.
    Huff V, Miwa H, Haber DA, et al. Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT.Am J Hum Genet. 1991;48:997–1003.Google Scholar
  8. 8.
    Pelletier J, Bruening W, Li FP, et al. Wt1 mutations contribute to abnormal genital system development and hereditary Wilms’ tumour.Nature. 1991;353:431–4.Google Scholar
  9. 9.
    Henry I, Bonaiti-Pellie C, Chehensse V, et al. Uniparental paternal disomy in a genetic cancer-predisposing syndrome.Nature. 1991; 351:665–667.Google Scholar
  10. 10.
    Grundy P, Telzerow P, Paterson MC, et al. Chromosome 11 uniparental isodisomy predisposing to embryonal neoplasms.Lancet. 1991;338:1079–1080.Google Scholar
  11. 11.
    Weksberg R, Shen DR, Fei YL, Song QL, Squire J. Disruption of insulin-like growth factor 2 imprinting in Beckwith-Wiedemann syndrome.Nat Genet. 1993;5:143–150.Google Scholar
  12. 12.
    Ohlsson R, Nystrom A, Pfeifer-Ohlsson S, et al. IGF2 is parentally imprinted during human embryogenesis and in the Beckwith-Wiedemann syndrome.Nat Genet. 1993;4:94–97.Google Scholar
  13. 13.
    Ogawa O, Becroft DM, Morison IM, et al. Constitutional relaxation of insulin-like growth factor II gene imprinting associated with Wilms’ tumour and gigantism.Nat Genet. 1993;5:408–412.Google Scholar
  14. 14.
    Matsuoka S, Thompson JS, Edwards MC, et al. Imprinting of the gene encoding a human cyclin-dependent kinase inhibitor, p57KIP2, on chromosome 11p15.Proc Natl Acad Sci U S A. 1996; 93:3026–3030.Google Scholar
  15. 15.
    Bartolomei MS, Zemel S, Tilghman SM. Parental imprinting of the mouse H19 gene.Nature. 1991;351:153–155.Google Scholar
  16. 16.
    Pelletier J, Bruening W, Kashtan CE, et al. Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.Cell. 1991;67: 437–447.Google Scholar
  17. 17.
    Bardeesy N, Zabel B, Schmitt K, Pelletier J. WT1 mutations associated with incomplete Denys-Drash syndrome define a domain predicted to behave in a dominant-negative fashion.Genomics.1994; 21:663–664.Google Scholar
  18. 18.
    Heathcott RW, Morison IM, Gubler MC, Corbett R, Reeve AE. A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X.Hum Mutat. 2002;19:462.Google Scholar
  19. 19.
    Little M, Carman G, Donaldson E. Novel WT1 exon 9 mutation (D396Y) in a patient with early onset Denys Drash syndrome.Hum Mutat. 2000;15:389.Google Scholar
  20. 20.
    Ohta S, Ozawa T, Izumino K, Sakuragawa N, Fuse H. A novel missense mutation of the Wt1 gene causing Denys-Drash syndrome with exceptionally mild renal manifestations.J Urol. 2000;163:1857–1858.Google Scholar
  21. 21.
    Patek CE, Little MH, Fleming S, et al. A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome.Proc Natl Acad Sci U S A. 1999;96: 2931–2936.Google Scholar
  22. 22.
    Sakai A, Tadokoro K, Yanagisawa H, et al. A novel mutation of the WT1 gene (a tumor suppressor gene for Wilms’ tumor) in a patient with Denys-Drash syndrome.Hum Mol Genet. 1993;2:1969–1970.Google Scholar
  23. 23.
    Swiatecka-Urban A, Mokrzycki MH, Kaskel F, Da Silva F, Denamur E. Novel WT1 mutation (C388Y) in a female child with Denys-Drash syndrome.Pediatr Nephrol. 2001;16:627–630.Google Scholar
  24. 24.
    Moffett P, Bruening W, Nakagama H, et al. Antagonism of WT1 activity by protein self-association.Proc Natl Acad Sci U S A. 1995; 92:11105–11109.Google Scholar
  25. 25.
    Reddy JC, Morris JC, Wang J, et al. WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins.J Biol Chem. 1995;270:10878–10884.Google Scholar
  26. 26.
    Klamt B, Koziell A, Poulat F, et al. Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/—KTS splice isoforms.Hum Mol Genet. 1998;7:709–714.Google Scholar
  27. 27.
    Barbaux S, Niaudet P, Gubler MC, et al. Donor splice-site mutations in WT1 are responsible for Frasier syndrome.Nat Genet.1997;17:467–470.Google Scholar
  28. 28.
    Varanasi R, Bardeesy N, Ghahremani M, et al. Fine structure analysis of the WT1 gene in sporadic Wilms tumors.Proc Natl Acad Sci U S A. 1994;91:3554–3558.Google Scholar
  29. 29.
    Little MH, Prosser J, Condie A, et al. Zinc finger point mutations within the WT1 gene in Wilms tumor patients.Proc Natl Acad Sci U S A. 1992;89:4791–4795.Google Scholar
  30. 30.
    Coppes MJ, Liefers GJ, Paul P,Yeger H,Williams BR. Homozygous somatic WT1 point mutations in sporadic unilateral Wilms tumor.Proc Natl Acad Sci U S A. 1993;90:1416–1419.Google Scholar
  31. 31.
    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.Google Scholar
  32. 32.
    Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB. The expression of the Wilms’ tumour gene, WT1, in the developing mammalian embryo.Mech Dev. 1993;40:85–97.Google Scholar
  33. 33.
    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.Google Scholar
  34. 34.
    Pelletier J, Schalling M, Buckler AJ, et al. Expression of the Wilms’ tumor gene WT1 in the murine urogenital system.Genes Dev. 1991; 5:1345–1356.Google Scholar
  35. 35.
    Pritchard-Jones K, Fleming S, Davidson D, et al. The candidate Wilms’ tumour gene is involved in genitourinary development.Nature. 1990;346:194–197.Google Scholar
  36. 36.
    Menssen HD, Renkl HJ, 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.Google Scholar
  37. 37.
    Miwa H, Beran M, Saunders GF. Expression of the Wilms’ tumor gene (WT1) in human leukemias.Leukemia. 1992;6:405–409.Google Scholar
  38. 38.
    Inoue K, Sugiyama H, Ogawa 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.Google Scholar
  39. 39.
    King-Underwood L, Renshaw J, Pritchard-Jones K. Mutations in the Wilms’ tumor gene WT1 in leukemias.Blood. 1996;87:2171–2179.Google Scholar
  40. 40.
    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.Google Scholar
  41. 41.
    Maurer U, Brieger J, Weidmann E, et al. 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.Google Scholar
  42. 42.
    Baird PN, Simmons PJ. Expression of the Wilms’ tumor gene (WT1) in normal hemopoiesis.Exp Hematol. 1997;25:312–320.Google Scholar
  43. 43.
    Deuel TF, Guan LS, Wang ZY. Wilms’ tumor gene product WT1 arrests macrophage differentiation of HL-60 cells through its zincfinger domain.Biochem Biophys Res Commun. 1999;254:192–196.Google Scholar
  44. 44.
    Svedberg H, Chylicki K, Baldetorp B, Rauscher FJ 3rd, 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.Google Scholar
  45. 45.
    Smith SI, Weil D, Johnson GR, Boyd AW, Li CL. Expression of the Wilms’ tumor suppressor gene, WT1, is upregulated by leukemia inhibitory factor and induces monocytic differentiation in M1 leukemic cells.Blood. 1998;91:764–773.Google Scholar
  46. 46.
    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.Google Scholar
  47. 47.
    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.Google Scholar
  48. 48.
    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.Google Scholar
  49. 49.
    Kreidberg JA, Sariola H, Loring JM, et al. WT-1 is required for early kidney development.Cell. 1993;74:679–691.Google Scholar
  50. 50.
    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.Google Scholar
  51. 51.
    Gaiger A, Schmid D, Heinze G, 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.Google Scholar
  52. 52.
    Takahashi T, Yamamoto R, Tanaka K, Kamada N, Miyagawa K. Mutation analysis of the WT1 gene in secondary leukemia.Leukemia. 2000;14:1316–1317.Google Scholar
  53. 53.
    Miyagawa K, Hayashi Y, Fukuda T, et al. Mutations of the WT1 gene in childhood nonlymphoid hematological malignancies.Genes Chromosomes Cancer. 1999;25:176–183.Google Scholar
  54. 54.
    Silberstein GB, Van Horn K, Strickland P, Roberts CTJr, 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.Google Scholar
  55. 55.
    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.Google Scholar
  56. 56.
    Park S, Schalling M, Bernard A, et al.The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma.Nat Genet. 1993;4:415–420.Google Scholar
  57. 57.
    Walker C, Rutten F, Yuan X, et al. Wilms’ tumor suppressor gene expression in rat and human mesothelioma.Cancer Res. 1994;54: 3101–3106.Google Scholar
  58. 58.
    Amin KM, Litzky LA, Smythe WR, et al. Wilms’ tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma.Am J Pathol. 1995;146:344–356.Google Scholar
  59. 59.
    Foster MR, Johnson JE, Olson SJ, Allred DC. Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas.Arch Pathol Lab Med. 2001;125:1316–1320.Google Scholar
  60. 60.
    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.Google Scholar
  61. 61.
    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.Google Scholar
  62. 62.
    Shimizu M, Toki T, Takagi Y, Konishi I, Fujii S. Immunohistochemical detection of the Wilms’ tumor gene (WT1) in epithelial ovarian tumors.Int J Gynecol Pathol. 2000;19:158–163.Google Scholar
  63. 63.
    Dennis SL, Manji SS, Carrington DP, et al. Expression and mutation analysis of the Wilms’ tumor 1 gene in human neural tumors.Int J Cancer. 2002;97:713–715.Google Scholar
  64. 64.
    Gerald WL, Ladanyi M, de Alava E, et al. Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants.J Clin Oncol. 1998;16:3028–3036.Google Scholar
  65. 65.
    Ladanyi M, Gerald W. Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor.Cancer Res. 1994;54: 2837–2840.Google Scholar
  66. 66.
    Ohno T, Ouchida M, Lee L, et al. The EWS gene, involved in Ewing family of tumors, malignant melanoma of soft parts and desmoplastic small round cell tumors, codes for an RNA binding protein with novel regulatory domains.Oncogene. 1994;9:3087–3097.Google Scholar
  67. 67.
    Gerald WL, Rosai J, Ladanyi M. Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.Proc Natl Acad Sci U S A. 1995;92:1028–1032.Google Scholar
  68. 68.
    Lee SB, Kolquist KA, Nichols K, et al. The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour.Nat Genet. 1997;17:309–313.Google Scholar
  69. 69.
    Hosen N, Sonoda Y, Oji Y, 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.Google Scholar
  70. 70.
    Mundlos S, Pelletier J, Darveau A, et al. Nuclear localization of the protein encoded by the Wilms’ tumor gene WT1 in embryonic and adult tissues.Development. 1993;119:1329–1341.Google Scholar
  71. 71.
    Francke U, Holmes LB, Atkins L, Riccardi VM. Aniridia-Wilms’ tumor association: evidence for specific deletion of 11p13.Cytogenet Cell Genet. 1979;24:185–192.Google Scholar
  72. 72.
    Riccardi VM, Sujansky E, Smith AC, Francke U. Chromosomal imbalance in the Aniridia-Wilms’ tumor association: 11p interstitial deletion.Pediatrics. 1978;61:604–610.Google Scholar
  73. 73.
    Park S, Bernard A, Bove KE, et al. Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms’ tumour.Nat Genet. 1993;5: 363–367.Google Scholar
  74. 74.
    Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics.Trends Genet. 2000;16:168–174.Google Scholar
  75. 75.
    Laux DE, Curran EM, Welshons WV, Lubahn DB, Huang TH. Hypermethylation of the Wilms’ tumor suppressor gene CpG island in human breast carcinomas.Breast Cancer Res Treat. 1999; 56:35–43.Google Scholar
  76. 76.
    Huang TH, Laux DE, Hamlin BC, et al. Identification of DNA methylation markers for human breast carcinomas using the methylation-sensitive restriction fingerprinting technique.Cancer Res. 1997;57:1030–1034.Google Scholar
  77. 77.
    Mares J, Kriz V, Weinhausel A, et al. Methylation changes in promoter and enhancer regions of the WT1 gene in Wilms’ tumours.Cancer Lett. 2001;166:165–171.Google Scholar
  78. 78.
    Hewitt SM, Hamada S, McDonnell TJ, Rauscher FJ 3rd, 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.Google Scholar
  79. 79.
    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.Google Scholar
  80. 80.
    Englert C, Maheswaran S, Garvin AJ, Kreidberg J, Haber DA. Induction of p21 by the Wilms’ tumor suppressor gene WT1.Cancer Res. 1997;57:1429–1434.Google Scholar
  81. 81.
    Gashler AL, Bonthron DT, Madden SL, et al. 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.Google Scholar
  82. 82.
    Wang ZY, Madden SL, Deuel TF, Rauscher FJ 3rd. The Wilms’ tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene.J Biol Chem. 1992;267:21999–22002.Google Scholar
  83. 83.
    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.Google Scholar
  84. 84.
    Drummond IA, Madden SL, Rohwer-Nutter P, et al. Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1.Science. 1992;257:674–678.Google Scholar
  85. 85.
    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;90:5828–5832.Google Scholar
  86. 86.
    Adachi Y, Matsubara S, Pedraza C, et al. Midkine as a novel target gene for the Wilms’ tumor suppressor gene (WT1).Oncogene. 1996;13:2197–2203.Google Scholar
  87. 87.
    Dey BR, Sukhatme VP, Roberts AB, et al. Repression of the transforming growth factor-beta 1 gene by the Wilms’ tumor suppressor WT1 gene product.Mol Endocrinol. 1994;8:595–602.Google Scholar
  88. 88.
    McCoy C, Smith DE, Cornwell MM. 12-O-tetradecanoylphorbol-13-acetate activation of the MDR1 promoter is mediated by EGR1.Mol Cell Biol. 1995;15:6100–6108.Google Scholar
  89. 89.
    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.Google Scholar
  90. 90.
    Loeb DM, Korz D, Katselnelson M, Burwell EA, Friedman AD, Sukumar S. Cyclin E is a target of WT1 transcriptional repression.J Biol Chem. 2002;277:19627–19632.Google Scholar
  91. 91.
    Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, et al. Wilms’ tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.Cell. 1998;93:445–454.Google Scholar
  92. 92.
    Shimamura R, Fraizer GC, Trapman J, Lau YfC, Saunders GF. The Wilms’ tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Mullerian-inhibiting substance, and the androgen receptor.Clin Cancer Res. 1997;3:2571–2580.Google Scholar
  93. 93.
    Martinerie C, Chevalier G, Rauscher FJ 3rd, Perbal B. Regulation of nov by WT1: A potential role for nov in nephrogenesis.Onco-gene. 1996;12:1479–1492.Google Scholar
  94. 94.
    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.Google Scholar
  95. 95.
    Harrington MA, Konicek B, Song A, et al. Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms’ tumor locus.J Biol Chem. 1993;268:21271–21275.Google Scholar
  96. 96.
    Thate C, Englert C, Gessler M. Analysis of WT1 target gene expression in stably transfected cell lines.Oncogene. 1998;17:1287–1294.Google Scholar
  97. 97.
    Lee TH, Pelletier J. Functional characterization of WT1 binding sites within the human vitamin D receptor gene promoter.Physiol Genomics. 2001;7:187–200.Google Scholar
  98. 98.
    Wagner KD,Wagner N, Sukhatme VP, Scholz H. Activation of vitamin D receptor by the Wilms’ tumor gene product mediates apoptosis of renal cells.J Am Soc Nephrol. 2001;12:1188–1196.Google Scholar
  99. 99.
    Maurer U, Jehan F, Englert C, et al. The Wilms’ tumor gene product (WT1) modulates the response to 1,25-dihydroxyvitamin D3 by induction of the vitamin D receptor.J Biol Chem. 2001;276: 3727–3732.Google Scholar
  100. 100.
    Goodyer P, Dehbi M, Torban E, Bruening W, Pelletier J. Repression of the retinoic acid receptor-alpha gene by the Wilms’ tumor suppressor gene product, WT1.Oncogene. 1995;10:1125–1129.Google Scholar
  101. 101.
    Vainio S, Lehtonen E, Jalkanen M, Bernfield M, Saxen L. Epithelial-mesenchymal interactions regulate the stage-specific expression of a cell surface proteoglycan, syndecan, in the developing kidney.Dev Biol. 1989;134:382–391.Google Scholar
  102. 102.
    Cook DM, Hinkes MT, Bernfield M, Rauscher FJ 3rd. Transcriptional activation of the syndecan-1 promoter by the Wilms’ tumor protein WT1.Oncogene. 1996;13:1789–1799.Google Scholar
  103. 103.
    Hosono S, Gross I, English MA, et al. E-cadherin is a WT1 target gene.J Biol Chem. 2000;275:10943–10953.Google Scholar
  104. 104.
    Berx G, Van Roy F. The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression.Breast Cancer Res. 2001;3:289–293.Google Scholar
  105. 105.
    Lee SB, Huang K, Palmer R, et al. The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin.Cell. 1999;98:663–673.Google Scholar
  106. 106.
    Evron E, Dooley WC, Umbricht CB, et al. Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR.Lancet. 2001;357:1335–1336.Google Scholar
  107. 107.
    Goldstein NS, Bassi D, Uzieblo A. WT1 is an integral component of an antibody panel to distinguish pancreaticobiliary and some ovarian epithelial neoplasms.Am J Clin Pathol. 2001;116:246–252.Google Scholar
  108. 108.
    Goldstein NS, Uzieblo A. WT1 immunoreactivity in uterine papillary serous carcinomas is different from ovarian serous carcinomas.Am J Clin Pathol. 2002;117:541–545.Google Scholar
  109. 109.
    Hecht JL, Lee BH, Pinkus JL, Pinkus GS. The value of Wilms tumor susceptibility gene 1 in cytologic preparations as a marker for malignant mesothelioma.Cancer. 2002;96:105–109.Google Scholar
  110. 110.
    Menssen HD, Renkl HJ, Rieder H, et al. Distinction of eosino-philic leukaemia from idiopathic hypereosinophilic syndrome by analysis of Wilms’ tumour gene expression.Br J Haematol. 1998; 101:325–334.Google Scholar
  111. 111.
    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.Google Scholar
  112. 112.
    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.Google Scholar
  113. 113.
    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.Google Scholar

Copyright information

© The Japanese Society of Hematology 2002

Authors and Affiliations

  • David M. Loeb
    • 1
  • Saraswati Sukumar
    • 2
  1. 1.Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  2. 2.Bunting-Blaustein Cancer Research BuildingBaltimore

Personalised recommendations