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

  • Suzie Ariyaratana (a1) and David M. Loeb (a1)
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.

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Corresponding author
*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
References
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128Ryan, G. et al. (1995) Repression of Pax-2 by WT1 during normal kidney development. Development 121, 867-875
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131Hosono, S. et al. (2000) E-cadherin is a WT1 target gene. J Biol Chem 275, 10943-10953
132Hossain, A. and Saunders, G.F. (2001) The human sex-determining gene SRY is a direct target of WT1. J Biol Chem 276, 16817-16823
133Kim, J. et al. (1999) The Wilms' tumor suppressor gene (wt1) product regulates Dax-1 gene expression during gonadal differentiation. Mol Cell Biol 19, 2289-2299
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, 651-659
135Palmer, R.E. et al. (2001) WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin. Curr Biol 11, 1805-1809
136Stanhope-Baker, P. et al. (2004) The Wilms tumor suppressor-1 target gene podocalyxin is transcriptionally repressed by p53. J Biol Chem 279, 33575-33585
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138Han, X. and Chesney, R.W. (2003) Regulation of taurine transporter gene (TauT) by WT1. FEBS Lett 540, 71-76
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, 41420-41430
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, 30760-30764
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, 8174-8182
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, 4695-4702
143Loeb, D.M. et al. (2002) Cyclin E is a target of WT1 transcriptional repression. J Biol Chem 277, 19627-19632
144Englert, C. et al. (1997) Induction of p21 by the Wilms' tumor suppressor gene WT1. Cancer Res 57, 1429-1434
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, 13258-13263
146Li, R.S. et al. (1999) Ornithine decarboxylase is a transcriptional target of tumor suppressor WT1. Exp Cell Res 247, 257-266
147Moshier, J.A. et al. (1996) Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1. Nucleic Acids Res 24, 1149-1157
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, 503-509
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This listing from the Atlas of Genetics and Cytogenetics in Oncology and Hematology neatly summarises much of what is known about the role of WT1 in human malignancy, with numerous links to external sources of further information:

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