The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes

Tamaki, Hiroya; Ogawa, Hiroyasu; Ohyashiki, Kazuma; Ohyashiki, J H; Iwama, Hiroshi; Inoue, Kazushi; Soma, Toshihiro; Oka, Y.; Tatekawa, Toyoshi; Oji, Yusuke; Tsuboi, Akihiro; Kim, Eh H.; Kawakami, Manabu; Fuchigami, Kengo; Tomonaga, Masao; Toyama, Keisuke; Aozasa, Katsuyuki; Kishimoto, Tomoya; Sugiyama, Haruo

doi:10.1038/sj.leu.2401341

Cited by 165 publications

(109 citation statements)

References 16 publications

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“…116 In a pediatric case with MDS successful withdrawal of immunosuppression due to an increase of WT1 was described: on day 263 after SCT the patient had an increase of the WT1 gene-expression level in the BM (16 000 copies per mg RNA) and in peripheral blood (3700 copies per mg RNA). Cytogenetics confirmed continuing complete cytogenetic remission (he had a trisomy 8 before SCT), and there was full DC.…”

Section: Myelodysplastic Syndromesmentioning

confidence: 99%

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

Bacher

Zander

Haferlach

et al. 2008

Bone Marrow Transplant

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Allogeneic SCT is important in myelodysplastic syndrome, the BCR-ABL-negative chronic myeloproliferative diseases (CMPDs) and in poor-risk AML. Techniques to monitor the minimal residual disease, for example, by PCR or immunophenotyping gain increasing importance in the post transplantation period as basis for improved and earlier therapeutic interventions in impending relapse. Recent markers such as the NPM1 mutations in AML or the JAK2V617F mutation in the CMPD can be exactly quantified by real-time PCR and were evaluated for their prognostic value in the post transplantation phase and for their utility to plan adoptive immunotherapy in case of molecular relapse. With respect to chimerism, new and very sensitive methods were introduced, for example, quantitative assessment of genetic polymorphisms by realtime PCR, but also methods here are still highly individualized. Only in CML, where SCT focuses now on poor-risk cases or cases of tyrosine kinase inhibitor failure, follow-up schedules are standardized. Standardization of the different diagnostic techniques and of the intervals in the post transplantation period is urgently needed also in other myeloid malignancies and should be focus of future studies.

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Section: Myelodysplastic Syndromesmentioning

confidence: 99%

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

Bacher

Zander

Haferlach

et al. 2008

Bone Marrow Transplant

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“…8 WT1 expression has been evaluated as a marker for risk stratification and MRD detection in AML. [1][2][3][4][5][11][12][13][14] However, contradictory reports refer to the value of WT1 hyperexpression for monitoring MRD during front-line chemotherapy and after allogeneic stem-cell transplantation. Although many authors describe a strong predictive value, 3,4,9,10,15 these findings could not be confirmed by others.…”

Section: Introductionmentioning

confidence: 99%

Standardization of WT1 mRNA quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study

Willasch

Gruhn²,

Coliva

et al. 2009

Leukemia

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A standardized, sensitive and universal method for minimal residual disease (MRD) detection in acute myeloid leukemia (AML) is still pending. Although hyperexpression of Wilms' tumor (WT1) gene transcript has been frequently proposed as an MRD marker in AML, wide comparability of the various methods used for evaluating WT1 expression has not been given. We established and standardized a multicenter approach for quantifying WT1 expression by quantitative reverse transcriptase PCR (qRT-PCR), on the basis of a primer/probe set combination at exons 6 and 7. In a series of quality-control rounds, we analyzed 69 childhood AML samples and 47 normal bone marrow (BM) samples from 4 participating centers. Differences in the individual WT1 expressions levels ranged within o0.5 log of the mean in 82% of the cases. In AML samples, the median WT1/1E þ 04 Abelson (ABL) expression was 3.5E þ 03 compared with that of 2.3E þ 01 in healthy BM samples. As 11.5% of childhood AML samples in this cohort harbored WT1 mutations in exon 7, the effect of mutations on WT1 expression has been investigated, showing that mutated cases expressed significantly higher WT1 levels than wild-type cases. Hence, our approach showed high reproducibility and applicability, even in patients with WT1 mutations; therefore, it can be widely used for the quantitation of WT1 expression in future clinical trials.

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“…[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. [9][10][11] Thus, depending on the cells and situations expressing WT1, it displays both anti-oncogenic and oncogenic characters. 12 Despite the fact that the oncogenic functions of WT1 have been well documented, its gene-expression mechanism remains undetermined.…”

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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The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes

Cited by 165 publications

References 16 publications

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

Standardization of WT1 mRNA quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study

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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