Possible regulation of Wilms’ tumour gene 1 (WT1) expression by the paired box genes PAX2 and PAX8 and by the haematopoietic transcription factor GATA‐1 in human acute myeloid leukaemias

Abstract

Summary. Overexpression of the embryonic transcription factor, Wilms' tumour protein 1 (WT1), is common in acute myeloid leukaemias (AML). Mutations of Wilms' tumour gene 1 (WT1) in AML are rare and WT1 expression may be increased by other transcription factors. PAX2, PAX8 and GATA-1 are known physiological regulators of WT1. In the present study, we analysed either bone marrow or blood samples of 43 AML patients for the expression levels of WT1, PAX2, PAX8 and GATA-1 by real-time reverse transcription polymerase chain reaction (LightCycler). Bone marrow samples of patients without haematological malignancies and stem cell preparation samples from healthy donors and lymphoma patients served as controls. PAX2 expression was found in 11 of 43 AML samples, with a clear correlation of PAX2 with WT1 expression levels observed. PAX8 expression was found in two additional samples. GATA-1 expression was detectable in 41 of 43 AML samples and also in all control samples; no significant differences between these groups were observed and no correlation of GATA-1 expression with WT1 expression levels was apparent. In conclusion, PAX2, and possibly PAX8, appears to be a candidate for the upregulation of WT1 in a proportion of AML, whereas GATA-1 expression cannot be explained as an inducer of WT1. In two-thirds of leukaemias from our series, the basis of WT1 upregulation cannot be explained by the simple upregulation of the known WT1 activators.

Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity

“…Upon repeated analysis, WT1 levels have remained low and in the same range as levels detected in the bone marrow of healthy subjects. 7 Potential side effects of vaccination with WT1 are of concern due to the low-level expression of WT1 in the kidney, and transiently during maturation in normal hematopoietic progenitor cells. 9 There are, however, several preclinical and clinical studies showing WT1-specific immunity in the absence of autoimmunity (reviewed in Rosenfeld et al 1 and Scheibenbogen et al 10 ).…”

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

“…16 To date, in addition to Sp1 and GATA-1, PAX2 and PAX8 are also reported to be the transcription factors that regulate WT1 gene expression. [17][18][19][20] Dehbi et al 17 reported the binding sites of PAX2 and PAX8 in the 5 0 promoter of WT1 gene. Zhang et al 20 indicated the importance of the intron 3 enhancer of WT1 gene, which was activated by GATA-1 and Myb.…”

Wilms' tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring

“…1,2,5 A possible imbalance in the ratio of the main WT1 isoforms in acute leukemia and its effect will require further investigation. 47,48 The WT1 protein possesses immunogenic properties and has been successfully tested as a target for antileukemic vaccines. 2,5,[49][50][51][52][53] The discrepancies between different authors and studies on the expression and role of WT1 in acute leukemia may result from the nonstandardized techniques of WT1 detection and quantification employed (qualitative PCR vs real-time quantitative PCR (RQ-PCR), relative vs absolute methods of the gene expression quantification, different control genes, type and number of negative/normal controls), the type of samples evaluated (bone marrow (BM) vs peripheral blood (PB)), as well as the size and character of the patient groups examined.…”