The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis

Suzie Ariyaratana; David M. Loeb

doi:10.1017/S1462399407000336

The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis

Published online by Cambridge University Press: 24 May 2007

Suzie Ariyaratana and

David M. Loeb

Show author details

Suzie Ariyaratana: Affiliation:
Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
David M. Loeb*: Affiliation:
Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
*: *Corresponding author: David M. Loeb, Pediatric Oncology, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, USA. Tel: +1 410 955 2457; Fax: +1 410 955 8897; E-mail: loebda@jhmi.edu

Article contents

Abstract
References

Get access

Rights & Permissions

Abstract

In addition to its loss playing a pivotal role in the development of a childhood kidney malignancy, the Wilms tumour 1 gene (WT1) has emerged as an important factor in normal and malignant haematopoiesis. Preferentially expressed in CD34+ haematopoietic progenitors and down-regulated in more-differentiated cells, the WT1 transcription factor has been implicated in regulation of apoptosis, proliferation and differentiation. Putative target genes, such as BCL2, MYC, A1 and cyclin E, may cooperate with WT1 to modulate cell growth. However, the effects of WT1 on target gene expression appear to be isoform-specific. Certain WT1 isoforms are over-represented in leukaemia, but the exact mechanisms underlying the role of WT1 in transformation remain unclear. The ubiquity of WT1 in haematological malignancies has led to efforts to exploit it as a marker for minimal residual disease and as a prognostic factor, with conflicting results. In vitro killing of tumour cells by WT1-specific CD8+ cytotoxic T lymphocytes facilitated design of Phase I vaccine trials that showed clinical regression of WT1-positive tumours. Alternative methods employing WT1-specific immunotherapy are being investigated and might ultimately be used to optimise multimodal therapy of haematological malignancies.

Type: Research Article
Information: Expert Reviews in Molecular Medicine , Volume 9 , Issue 14 , May 2007 , pp. 1 - 17

DOI: https://doi.org/10.1017/S1462399407000336 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Haber, D.A. et al. (1990) An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell 61, 1257-1269CrossRef Google Scholar

2Fraizer, G.C. et al. (1995) Expression of the tumor suppressor gene WT1 in both human and mouse bone marrow. Blood 86, 4704-4706CrossRef Google Scholar PubMed

3Baird, P.N. and Simmons, P.J. (1997) Expression of the Wilms' tumor gene (WT1) in normal hemopoiesis. Exp Hematol 25, 312-320Google Scholar PubMed

4Maurer, U. et al. (1997) The Wilms' tumor gene is expressed in a subset of CD34+ progenitors and downregulated early in the course of differentiation in vitro. Exp Hematol 25, 945-950Google Scholar

5Hosen, N. et al. (2002) 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 116, 409-420CrossRef Google Scholar PubMed

6Mundlos, S. et al. (1993) Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues. Development 119, 1329-1341CrossRef Google Scholar PubMed

7Oji, Y. et al. (2002) Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers. Int J Cancer 100, 297-303CrossRef Google Scholar PubMed

8Koesters, R. et al. (2004) WT1 is a tumor-associated antigen in colon cancer that can be recognized by in vitro stimulated cytotoxic T cells. Int J Cancer 109, 385-392CrossRef Google Scholar PubMed

9Oji, Y. et al. (2004) Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci 95, 583-587CrossRef Google Scholar PubMed

10Athale, U.H. et al. (2001) Use of reverse transcriptase polymerase chain reaction for diagnosis and staging of alveolar rhabdomyosarcoma, Ewing sarcoma family of tumors, and desmoplastic small round cell tumor. J Pediatr Hematol Oncol 23, 99-104CrossRef Google Scholar PubMed

11Amin, K.M. et al. (1995) Wilms' tumor 1 susceptibility (WT1) gene products are selectively expressed in malignant mesothelioma. Am J Pathol 146, 344-356Google Scholar PubMed

12Thorner, P. et al. (1999) Expression of WT1 in pediatric small cell tumors: report of two cases with a possible mesothelial origin. Pediatr Dev Pathol 2, 33-41CrossRef Google Scholar PubMed

13Miwa, H., Beran, M. and Saunders, G.F. (1992) Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 6, 405-409Google Scholar PubMed

14Inoue, K. et al. (1994) WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 84, 3071-3079CrossRef Google Scholar

15Bergmann, L. et al. (1997) High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 90, 1217-1225CrossRef Google Scholar PubMed

16King-Underwood, L. and Pritchard-Jones, K. (1998) Wilms' tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 91, 2961-2968CrossRef Google Scholar PubMed

17Miyagawa, K. et al. (1999) Mutations of the WT1 gene in childhood nonlymphoid hematological malignancies. Genes Chromosomes Cancer 25, 176-1833.0.CO;2-F>CrossRef Google Scholar PubMed

18Caricasole, A. et al. (1996) RNA binding by the Wilms tumor suppressor zinc finger proteins. Proc Natl Acad Sci U S A 93, 7562-7566CrossRef Google Scholar PubMed

19Bardeesy, N. and Pelletier, J. (1998) Overlapping RNA and DNA binding domains of the wt1 tumor suppressor gene product. Nucleic Acids Res 26, 1784-1792CrossRef Google Scholar PubMed

20Haber, D.A. et al. (1991) Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci U S A 88, 9618-9622CrossRef Google Scholar PubMed

21Renshaw, J., King-Underwood, L. and Pritchard-Jones, K. (1997) Differential splicing of exon 5 of the Wilms tumour (WTI) gene. Genes Chromosomes Cancer 19, 256-2663.0.CO;2-W>CrossRef Google Scholar PubMed

22Laity, J.H., Dyson, H.J. and Wright, P.E. (2000) Molecular basis for modulation of biological function by alternate splicing of the Wilms' tumor suppressor protein. Proc Natl Acad Sci U S A 97, 11932-11935CrossRef Google Scholar PubMed

23Rauscher, F.J. 3rd et al. (1990) Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. Science 250, 1259-1262CrossRef Google Scholar

24Reddy, J.C., Hosono, S. and Licht, J.D. (1995) The transcriptional effect of WT1 is modulated by choice of expression vector. J Biol Chem 270, 29976-29982CrossRef Google Scholar PubMed

25Reddy, J.C. et al. (1995) WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins. J Biol Chem 270, 10878-10884CrossRef Google Scholar PubMed

26Larsson, S.H. et al. (1995) Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell 81, 391-401CrossRef Google Scholar PubMed

27Englert, C. et al. (1995) Truncated WT1 mutants alter the subnuclear localization of the wild-type protein. Proc Natl Acad Sci U S A 92, 11960-11964CrossRef Google Scholar PubMed

28Davies, R.C. et al. (1998) WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes. Genes Dev 12, 3217-3225CrossRef Google Scholar

29Markus, M.A. et al. (2006) WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo. Exp Cell Res 312, 3379-3388CrossRef Google Scholar PubMed

30Ladomery, M.R. et al. (1999) Presence of WT1, the Wilm's tumor suppressor gene product, in nuclear poly(A)(+) ribonucleoprotein. J Biol Chem 274, 36520-36526CrossRef Google Scholar

31Morrison, A.A. et al. (2006) The Wilms tumour suppressor protein WT1 (+KTS isoform) binds alpha-actinin 1 mRNA via its zinc-finger domain. Biochem Cell Biol 84, 789-798CrossRef Google Scholar PubMed

32Bruening, W. and Pelletier, J. (1996) A non-AUG translational initiation event generates novel WT1 isoforms. J Biol Chem 271, 8646-8654CrossRef Google Scholar PubMed

33Hossain, A. et al. (2006) N-terminally truncated WT1 protein with oncogenic properties overexpressed in leukemia. J Biol Chem 281, 28122-28130CrossRef Google Scholar PubMed

34Madden, S.L. et al. (1991) Transcriptional repression mediated by the WT1 Wilms tumor gene product. Science 253, 1550-1553CrossRef Google Scholar PubMed

35Wang, Z.Y. et al. (1993) A second transcriptionally active DNA-binding site for the Wilms tumor gene product, WT1. Proc Natl Acad Sci U S A 90, 8896-8900CrossRef Google Scholar PubMed

36Englert, C. et al. (1995) WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. Embo J 14, 4662-4675CrossRef Google Scholar PubMed

37Thate, C., Englert, C. and Gessler, M. (1998) Analysis of WT1 target gene expression in stably transfected cell lines. Oncogene 17, 1287-1294CrossRef Google Scholar PubMed

38Wagner, N. et al. (2004) The major podocyte protein nephrin is transcriptionally activated by the Wilms' tumor suppressor WT1. J Am Soc Nephrol 15, 3044-3051CrossRef Google Scholar PubMed

39Kirschner, K.M. et al. (2006) The Wilms tumor suppressor Wt1 promotes cell adhesion through transcriptional activation of the alpha4integrin gene. J Biol Chem 281, 31930-31939Google Scholar PubMed

40Park, S. et al. (1993) The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma. Nat Genet 4, 415-420CrossRef Google Scholar

41Armstrong, J.F. et al. (1993) The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo. Mech Dev 40, 85-97CrossRef Google Scholar PubMed

42Maurer, U. et al. (1997) Wilms tumor gene (wt1) mRNA is equally expressed in blast cells from acute myeloid leukemia and normal CD34+ progenitors. Blood 90, 4230-4232CrossRef Google Scholar PubMed

43Inoue, K. et al. (1997) Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 89, 1405-1412CrossRef Google Scholar PubMed

44Phelan, S.A., Lindberg, C. and Call, K.M. (1994) Wilms' tumor gene, WT1, mRNA is down-regulated during induction of erythroid and megakaryocytic differentiation of K562 cells. Cell Growth Differ 5, 677-686Google Scholar PubMed

45Sekiya, M. et al. (1994) Downregulation of Wilms' tumor gene (wt1) during myelomonocytic differentiation in HL60 cells. Blood 83, 1876-1882CrossRef Google Scholar PubMed

46Svedberg, H. et al. (1998) Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program. Oncogene 16, 925-932CrossRef Google Scholar PubMed

47Inoue, K. et al. (1998) Wilms' tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 91, 2969-2976CrossRef Google Scholar PubMed

48Alberta, J.A. et al. (2003) Role of the WT1 tumor suppressor in murine hematopoiesis. Blood 101, 2570-2574CrossRef Google Scholar PubMed

49Siehl, J.M. et al. (2004) Expression of Wilms' tumor gene 1 at different stages of acute myeloid leukemia and analysis of its major splice variants. Ann Hematol 83, 745-750CrossRef Google Scholar PubMed

50Trka, J. et al. (2002) 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 16, 1381-1389CrossRef Google Scholar PubMed

51Patmasiriwat, P. et al. (1999) WT1 and GATA1 expression in myelodysplastic syndrome and acute leukemia. Leukemia 13, 891-900CrossRef Google Scholar PubMed

52Loeb, D.M. et al. (2003) An isoform of the Wilms' tumor suppressor gene potentiates granulocytic differentiation. Leukemia 17, 965-971CrossRef Google Scholar PubMed

53Ellisen, L.W. et al. (2001) The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. Embo J 20, 1897-1909CrossRef Google Scholar PubMed

54Oji, Y. et al. (2003) Overexpression of the Wilms' tumor gene WT1 in head and neck squamous cell carcinoma. Cancer Sci 94, 523-529CrossRef Google Scholar PubMed

55Ueda, T. et al. (2003) Overexpression of the Wilms' tumor gene WT1 in human bone and soft-tissue sarcomas. Cancer Sci 94, 271-276CrossRef Google Scholar PubMed

56Ito, K. et al. (2006) Antiapoptotic function of 17AA(+)WT1 (Wilms' tumor gene) isoforms on the intrinsic apoptosis pathway. Oncogene 25, 4217-4229CrossRef Google Scholar PubMed

57Nishida, S. et al. (2006) AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 107, 3303-3312CrossRef Google Scholar PubMed

58Breslow, N.E. et al. (1995) Second malignant neoplasms following treatment for Wilm's tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 13, 1851-1859CrossRef Google Scholar PubMed

59Shearer, P. et al. (2001) Secondary acute myelogenous leukemia in patients previously treated for childhood renal tumors: a report from the National Wilms Tumor Study Group. J Pediatr Hematol Oncol 23, 109-111CrossRef Google Scholar PubMed

60Pritchard-Jones, K., Renshaw, J. and King-Underwood, L. (1994) The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient. Hum Mol Genet 3, 1633-1637CrossRef Google Scholar

61King-Underwood, L., Renshaw, J. and Pritchard-Jones, K. (1996) Mutations in the Wilms' tumor gene WT1 in leukemias. Blood 87, 2171-2179CrossRef Google Scholar PubMed

62Carapeti, M., Goldman, J.M. and Cross, N.C. (1997) Dominant-negative mutations of the Wilms' tumour predisposing gene (WT1) are infrequent in CML blast crisis and de novo acute leukaemia. Eur J Haematol 58, 346-349CrossRef Google Scholar PubMed

63Summers, K.S.J., Kakkas, I., Smith, M., Smith, L.L., Macdougall, F., Cavenagh, J., Bonnet, D., Young, B.D., Lister, T.A. and Fitzgibbon, J. (2007) Wilms' tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 21, 550-551CrossRef Google Scholar PubMed

64Kreidberg, J.A. et al. (1993) WT-1 is required for early kidney development. Cell 74, 679-691CrossRef Google Scholar PubMed

65Mayo, M.W. et al. (1999) WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. Embo J 18, 3990-4003CrossRef Google Scholar PubMed

66Murata, Y. et al. (1997) The Wilms tumor suppressor gene WT1 induces G1 arrest and apoptosis in myeloblastic leukemia M1 cells. FEBS Lett 409, 41-45CrossRef Google Scholar PubMed

67Renshaw, J. et al. (2004) Disruption of WT1 gene expression and exon 5 splicing following cytotoxic drug treatment: antisense down-regulation of exon 5 alters target gene expression and inhibits cell survival. Mol Cancer Ther 3, 1467-1484CrossRef Google Scholar PubMed

68Algar, E.M. et al. (1996) A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines. Oncogene 12, 1005-1014Google Scholar PubMed

69Barragan, E. et al. (2004) Prognostic implications of Wilms' tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 89, 926-933Google Scholar PubMed

70Yanada, M. et al. (2004) Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia. Leuk Lymphoma 45, 1803-1808CrossRef Google Scholar PubMed

71Schmid, D. et al. (1997) Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia. Leukemia 11, 639-643CrossRef Google Scholar PubMed

72Gaiger, A. et al. (1999) 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 63, 86-93CrossRef Google Scholar PubMed

73Rodrigues, P.C. et al. (2006) Prognostic significance of WT1 gene expression in pediatric acute myeloid leukemia. Pediatr Blood CancerGoogle Scholar

74Gaiger, A. et al. (1998) Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia 12, 1886-1894CrossRef Google Scholar PubMed

75Kreuzer, K.A. et al. (2001) Fluorescent 5'-exonuclease assay for the absolute quantification of Wilms' tumour gene (WT1) mRNA: implications for monitoring human leukaemias. Br J Haematol 114, 313-318CrossRef Google Scholar PubMed

76Ogawa, H. et al. (2004) WT1 gene transcript assay for relapse in acute leukemia after transplantation. Leuk Lymphoma 45, 1747-1753CrossRef Google Scholar PubMed

77Ogawa, H. et al. (2003) The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 101, 1698-1704CrossRef Google Scholar PubMed

78Ostergaard, M. et al. (2004) WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients - results from a single-centre study. Br J Haematol 125, 590-600CrossRef Google Scholar PubMed

79Tamaki, H. et al. (2003) Monitoring minimal residual disease in leukemia using real-time quantitative polymerase chain reaction for Wilms tumor gene (WT1). Int J Hematol 78, 349-356CrossRef Google Scholar PubMed

80Cilloni, D. et al. (2002) 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 16, 2115-2121CrossRef Google Scholar PubMed

81Cilloni, D. and Saglio, G. (2004) WT1 as a universal marker for minimal residual disease detection and quantification in myeloid leukemias and in myelodysplastic syndrome. Acta Haematol 112, 79-84CrossRef Google Scholar PubMed

82Inoue, K. et al. (1996) Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood 88, 2267-2278CrossRef Google Scholar PubMed

83Lapillonne, H. et al. (2006) High WT1 expression after induction therapy predicts high risk of relapse and death in pediatric acute myeloid leukemia. J Clin Oncol 24, 1507-1515CrossRef Google Scholar PubMed

84Miyamura, T. et al. (2004) Clinical significance of minimal residual disease in childhood acute myeloid leukemia. Int J Hematol 79, 243-249CrossRef Google Scholar PubMed

85Tamura, K. et al. (2006) Successful rapid discontinuation of immunosuppressive therapy at molecular relapse after allogeneic bone marrow transplantation in a pediatric patient with myelodysplastic syndrome. Am J Hematol 81, 139-141CrossRef Google Scholar

86Fisk, B. et al. (1995) Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med 181, 2109-2117CrossRef Google Scholar PubMed

87Tsuboi, A. et al. (2000) Cytotoxic T-lymphocyte responses elicited to Wilms' tumor gene WT1 product by DNA vaccination. J Clin Immunol 20, 195-202CrossRef Google Scholar PubMed

88Gaiger, A. et al. (2000) Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood 96, 1480-1489CrossRef Google Scholar PubMed

89Elisseeva, O.A. et al. (2002) Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. Blood 99, 3272-3279CrossRef Google Scholar PubMed

90Ohminami, H., Yasukawa, M. and Fujita, S. (2000) HLA class I-restricted lysis of leukemia cells by a CD8(+) cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood 95, 286-293CrossRef Google Scholar PubMed

91Sugiyama, H. (2005) Cancer immunotherapy targeting Wilms' tumor gene WT1 product. Expert Rev Vaccines 4, 503-512CrossRef Google Scholar PubMed

92Gao, L. et al. (2000) Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 95, 2198-2203CrossRef Google Scholar PubMed

93Guo, Y. et al. (2005) Direct recognition and lysis of leukemia cells by WT1-specific CD4+ T lymphocytes in an HLA class II-restricted manner. Blood 106, 1415-1418CrossRef Google Scholar

94Oka, Y. et al. (2004) Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci U S A 101, 13885-13890CrossRef Google Scholar PubMed

95Mailander, V. et al. (2004) Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity. Leukemia 18, 165-166CrossRef Google Scholar PubMed

96Roddie, H. et al. (2006) Phase I/II study of vaccination with dendritic-like leukaemia cells for the immunotherapy of acute myeloid leukaemia. Br J Haematol 133, 152-157CrossRef Google Scholar PubMed

97Nakajima, H. et al. (2004) WT1 peptide vaccination combined with BCG-CWS is more efficient for tumor eradication than WT1 peptide vaccination alone. Cancer Immunol Immunother 53, 617-624CrossRef Google Scholar PubMed

98Oka, Y. et al. (2006) Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers. Curr Med Chem 13, 2345-2352Google Scholar PubMed

99Wang, Z.Y. et al. (1995) Products of alternatively spliced transcripts of the Wilms' tumor suppressor gene, wt1, have altered DNA binding specificity and regulate transcription in different ways. Oncogene 10, 415-422Google Scholar PubMed

100Drummond, I.A. et al. (1992) Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1. Science 257, 674-678CrossRef Google Scholar PubMed

101Nichols, K.E. et al. (1995) WT1 induces expression of insulin-like growth factor 2 in Wilms' tumor cells. Cancer Res 55, 4540-4543Google Scholar PubMed

102Lee, Y.I. and Kim, S.J. (1996) Transcriptional repression of human insulin-like growth factor-II P4 promoter by Wilms' tumor suppressor WT1. DNA Cell Biol 15, 99-104CrossRef Google Scholar PubMed

103Wang, Z.Y. et al. (1992) The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene. J Biol Chem 267, 21999-22002CrossRef Google Scholar PubMed

104Gashler, A.L. et al. (1992) Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1. Proc Natl Acad Sci U S A 89, 10984-10988CrossRef Google Scholar PubMed

105Harrington, M.A. et al. (1993) Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms' tumor locus. J Biol Chem 268, 21271-21275CrossRef Google Scholar PubMed

106Dey, B.R. et al. (1994) Repression of the transforming growth factor-beta 1 gene by the Wilms' tumor suppressor WT1 gene product. Mol Endocrinol 8, 595-602Google Scholar PubMed

107Lee, S.B. et al. (1999) The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell 98, 663-673CrossRef Google Scholar PubMed

108Hsu, S.Y. et al. (1995) Wilms' tumor protein WT1 as an ovarian transcription factor: decreases in expression during follicle development and repression of inhibin-alpha gene promoter. Mol Endocrinol 9, 1356-1366Google Scholar PubMed

109Adachi, Y. et al. (1996) Midkine as a novel target gene for the Wilms' tumor suppressor gene (WT1). Oncogene 13, 2197-2203Google Scholar PubMed

110Shimamura, R. et al. (1997) 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 3, 2571-2580Google Scholar PubMed

111Hossain, A. and Saunders, G.F. (2003) Role of Wilms tumor 1 (WT1) in the transcriptional regulation of the Mullerian-inhibiting substance promoter. Biol Reprod 69, 1808-1814CrossRef Google Scholar PubMed

112Stanhope-Baker, P. and Williams, B.R. (2000) Identification of connective tissue growth factor as a target of WT1 transcriptional regulation. J Biol Chem 275, 38139-38150CrossRef Google Scholar PubMed

113Werner, H. et al. (1994) Transcriptional repression of the insulin-like growth factor I receptor (IGF-I-R) gene by the tumor suppressor WT1 involves binding to sequences both upstream and downstream of the IGF-I-R gene transcription start site. J Biol Chem 269, 12577-12582CrossRef Google Scholar PubMed

114Werner, H. et al. (1993) 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 90, 5828-5832CrossRef Google Scholar PubMed

115Werner, H. et al. (1996) Regulation of insulin-like growth factor I receptor gene expression by the Wilms' tumor suppressor WT1. J Mol Neurosci 7, 111-123CrossRef Google Scholar PubMed

116Tajinda, K., Carroll, J. and Roberts, C.T. Jr. (1999) Regulation of insulin-like growth factor I receptor promoter activity by wild-type and mutant versions of the WT1 tumor suppressor. Endocrinology 140, 4713-4724CrossRef Google Scholar PubMed

117Wagner, N. et al. (2005) Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1. Genes Dev 19, 2631-2642CrossRef Google Scholar PubMed

118Lee, T.H. and Pelletier, J. (2001) Functional characterization of WT1 binding sites within the human vitamin D receptor gene promoter. Physiol Genomics 7, 187-200CrossRef Google Scholar PubMed

119Maurer, U. et al. (2001) The Wilms' tumor gene product (WT1) modulates the response to 1,25-dihydroxyvitamin D3 by induction of the vitamin D receptor. J Biol Chem 276, 3727-3732CrossRef Google Scholar PubMed

120Wagner, K.D. et al. (2001) Activation of vitamin D receptor by the Wilms' tumor gene product mediates apoptosis of renal cells. J Am Soc Nephrol 12, 1188-1196CrossRef Google Scholar PubMed

121Webster, N.J. et al. (1997) Differential effects of Wilms tumor WT1 splice variants on the insulin receptor promoter. Biochem Mol Med 62, 139-150CrossRef Google Scholar PubMed

122Liu, X.W. et al. (2001) The Wilms' tumor gene product WT1 mediates the down-regulation of the rat epidermal growth factor receptor by nerve growth factor in PC12 cells. J Biol Chem 276, 5068-5073CrossRef Google Scholar PubMed

123Goodyer, P. et al. (1995) Repression of the retinoic acid receptor-alpha gene by the Wilms' tumor suppressor gene product, wt1. Oncogene 10, 1125-1129Google Scholar PubMed

124Rupprecht, H.D. et al. (1994) The Wilms' tumor suppressor gene WT1 is negatively autoregulated. J Biol Chem 269, 6198-6206CrossRef Google Scholar PubMed

125Han, Y. et al. (2004) Transcriptional activation of c-myc proto-oncogene by WT1 protein. Oncogene 23, 6933-6941CrossRef Google Scholar PubMed

126Hewitt, S.M. et al. (1995) Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. Cancer Res 55, 5386-5389Google Scholar PubMed

127Udtha, M. et al. (2003) Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors. Oncogene 22, 3821-3826CrossRef Google Scholar PubMed

128Ryan, G. et al. (1995) Repression of Pax-2 by WT1 during normal kidney development. Development 121, 867-875CrossRef Google Scholar PubMed

129McCann, S. et al. (1995) Repression of the c-myb gene by WT1 protein in T and B cell lines. J Biol Chem 270, 23785-23789CrossRef Google Scholar

130Dejong, V. et al. (1999) The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun. Oncogene 18, 3143-3151CrossRef Google Scholar PubMed

131Hosono, S. et al. (2000) E-cadherin is a WT1 target gene. J Biol Chem 275, 10943-10953CrossRef Google Scholar PubMed

132Hossain, A. and Saunders, G.F. (2001) The human sex-determining gene SRY is a direct target of WT1. J Biol Chem 276, 16817-16823CrossRef Google Scholar PubMed

133Kim, J. et al. (1999) The Wilms' tumor suppressor gene (wt1) product regulates Dax-1 gene expression during gonadal differentiation. Mol Cell Biol 19, 2289-2299CrossRef Google Scholar PubMed

134Guo, J.K. et al. (2002) WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. Hum Mol Genet 11, 651-659CrossRef Google Scholar PubMed

135Palmer, R.E. et al. (2001) WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin. Curr Biol 11, 1805-1809CrossRef Google Scholar PubMed

136Stanhope-Baker, P. et al. (2004) The Wilms tumor suppressor-1 target gene podocalyxin is transcriptionally repressed by p53. J Biol Chem 279, 33575-33585CrossRef Google Scholar PubMed

137Sim, E.U. et al. (2002) Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1. Oncogene 21, 2948-2960CrossRef Google Scholar PubMed

138Han, X. and Chesney, R.W. (2003) Regulation of taurine transporter gene (TauT) by WT1. FEBS Lett 540, 71-76CrossRef Google Scholar PubMed

139Gross, I. et al. (2003) The receptor tyrosine kinase regulator Sprouty1 is a target of the tumor suppressor WT1 and important for kidney development. J Biol Chem 278, 41420-41430CrossRef Google Scholar PubMed

140Kinane, T.B. et al. (1995) LLC-PK1 cell growth is repressed by WT1 inhibition of G-protein alpha i-2 protooncogene transcription. J Biol Chem 270, 30760-30764CrossRef Google Scholar PubMed

141Morrison, D.J., English, M.A. and Licht, J.D. (2005) WT1 induces apoptosis through transcriptional regulation of the proapoptotic Bcl-2 family member Bak. Cancer Res 65, 8174-8182CrossRef Google Scholar PubMed

142Simpson, L.A. et al. (2006) The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy. Blood 107, 4695-4702CrossRef Google Scholar PubMed

143Loeb, D.M. et al. (2002) Cyclin E is a target of WT1 transcriptional repression. J Biol Chem 277, 19627-19632CrossRef Google Scholar PubMed

144Englert, C. et al. (1997) Induction of p21 by the Wilms' tumor suppressor gene WT1. Cancer Res 57, 1429-1434Google Scholar PubMed

145English, M.A. and Licht, J.D. (1999) Tumor-associated WT1 missense mutants indicate that transcriptional activation by WT1 is critical for growth control. J Biol Chem 274, 13258-13263CrossRef Google Scholar PubMed

146Li, R.S. et al. (1999) Ornithine decarboxylase is a transcriptional target of tumor suppressor WT1. Exp Cell Res 247, 257-266CrossRef Google Scholar PubMed

147Moshier, J.A. et al. (1996) Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1. Nucleic Acids Res 24, 1149-1157CrossRef Google Scholar PubMed

148Minc, E. et al. (1999) The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. J Biol Chem 274, 503-509CrossRef Google Scholar PubMed

Article contents

The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis

Abstract

Access options

References

References

Further reading, resources and contacts

This article has been cited by the following publications. This list is generated based on data provided by Crossref.

Article contents

The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis

Abstract

Access options

References

References

Further reading, resources and contacts

Save article to Kindle

Save article to Dropbox

Save article to Google Drive

Reply to: Submit a response

Your details

You have entered the maximum number of contributors

Conflicting interests