Wilms' tumour gene 1 (WT1) in human neoplasia

Keilholz, Ulrich; Menssen, H D; Gaiger, Alexander; Menke, Aswin; Oji, Yusuke; Oka, Y.; Scheibenbogen, Carmen; Stauss, Hans J.; Thiel, Eckhard; Sugiyama, Haruo

doi:10.1038/sj.leu.2403817

Cited by 82 publications

(69 citation statements)

References 43 publications

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“…In contrast, overexpression of the non-mutated Wilms' tumor gene 1 (WT1) is found in 89-100% 10,[17][18][19][20] of patients with AML and MDS, making this marker an ideal tool for monitoring MRD. WT1 expression has already been shown to be a helpful marker in patients with AML after chemotherapy, 19,[21][22][23] after autologous 24 and after conventional allogeneic HCT.…”

Section: Introductionmentioning

confidence: 99%

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Lange¹,

Hubmann²,

Burkhardt

et al. 2010

Leukemia

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Relapse of malignant disease remains the major complication in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC). In this study, we investigated the predictive value of disease-specific markers (DSMs), donor chimerism (DC) analysis of unsorted (UDC) or CD34 þ sorted cells and Wilms' tumor gene 1 (WT1) expression. Eighty-eight patients with AML or MDS were monitored after allogenic HCT following 2 Gy total-body irradiation with (n ¼ 84) or without (n ¼ 4) fludarabine 3 Â 30 mg/m 2 , followed by cyclosporin A and mycophenolate mofetil. DSMs were determined by fluorescence in situ hybridization (FISH) and WT1 expression by real-time polymerase chain reaction. Chimerism analysis was performed on unsorted or CD34 þ sorted cells, by FISH or short tandem repeat polymerase chain reaction. Twenty-one (24%) patients relapsed within 4 months after HCT. UDC, CD34 þ DC and WT1 expression were each significant predictors of relapse with sensitivities ranging from 53 to 79% and specificities of 82-91%. Relapse within 28 days was excluded almost entirely on the basis of WT1 expression combined with CD34 þ DC kinetics. Monitoring of WT1 expression and CD34 þ DC predict relapse of AML and MDS after RIC-HCT.

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Section: Introductionmentioning

confidence: 99%

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Lange¹,

Hubmann²,

Burkhardt

et al. 2010

Leukemia

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show abstract

“…The precise role of WT1 in hematopoiesis and its contribution to leukemogenesis are still uncertain, although it has been suggested that impairment of WT1 protein function could promote stem cell proliferation and induce a differentiation block of hematopoietic cells. 164,165 WT1 gene is highly expressed in various types of leukemias, particularly in AML, and therefore can be used for MRD monitoring in AML patients. Mutations in WT1 gene in AML were first reported in 1998 by King-Underwood et al 166 in about 10-15% of AML cases.…”

Section: Other Mutated Genesmentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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“…The gene product, WT1, represses the transcription of growth factors, growth factor receptors and other genes. [1][2][3] On the other hand, WT1 has been regarded as an oncogene for leukemia and some solid tumors because high expression levels of WT1 mRNA were observed in these diseases, and in vivo and in vitro studies showed the positive roles it plays in cell growth and transformation. [4][5][6][7][8] WT1 mRNA is reportedly a good clinical marker for disease progression, diagnosis and detection of the minimal residual diseases of myelodysplastic syndromes and leukemia.…”

Section: Introductionmentioning

confidence: 99%

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

et al. 2009

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Although oncogenic functions and the clinical significance of Wilms tumor 1 (WT1) have been extensively studied in acute leukemia, the regulatory mechanism of its transcription still remains to be determined. We found a significant correlation among the amounts of WT1, GATA-1 and GATA-2 mRNAs from leukemia and solid tumor cell lines. Overexpression and small interfering RNA (siRNA) transfection experiments of GATA-1 and GATA-2 showed that these GATA transcription factors could induce WT1 expression. Promoter analysis showed that the 5 0 promoter did not explain the different WT1 mRNA levels between cell lines. The 3 0 enhancer, especially the distal sites out of six putative GATA binding sites located within the region, but not the intron 3 enhancer, were essential for the WT1 mRNA level. Electrophoretic mobility shift assay (EMSA) showed both GATA-1 and GATA-2 bound to these GATA sites. Besides acute leukemia cell lines, solid tumor cell lines including, TYK-nu-cPr also showed a high level of WT1 mRNA. We showed that GATA-2 expression is a determinant of WT1 mRNA expression in both TYK-nu-cPr cells and HL60 cells without GATA-1 expression. Taken together, these results suggest that GATA-1 and/or GATA-2 binding to a GATA site of the 3 0 enhancer of WT1 played an important role in WT1 gene expression.

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Wilms' tumour gene 1 (WT1) in human neoplasia

Cited by 82 publications

References 43 publications

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

GATA-1 and GATA-2 binding to 3′ enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines

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