High Levels of Wilms' Tumor Gene (wt1) mRNA in Acute Myeloid Leukemias Are Associated With a Worse Long-Term Outcome

Abstract

The tumor suppressor gene wt1 (Wilms' tumor gene) encodes for a zinc finger DNA-binding protein with predominantly transcription repressing properties. Because wt1 has been shown to be expressed in the vast majority of patients with acute myeloid leukemias (AML), we investigated the relevance of wt-1 mRNA expression regarding prognosis and possible prediction of relapse during follow-up. Totally bone marrow-derived blasts of 139 AML patients (129 newly diagnosed AML patients, 22 AML patients again in first relapse, and 10 AML patients analyzed primarily in first relapse) were studied for wt1 mRNA expression. Seventy-seven patients were analyzed for wt1 mRNA expression during follow-up. wt1-specific reverse transcription-polymerase chain reaction (RT-PCR) was performed and the amplification product was visually classified as not, weakly, moderately, or strongly amplified, as described previously. PCR products were quantitated by competitive PCR using a shortened homologous wt1 construct standard in representative cases. The expression of wt1 transcripts was correlated to age, French-American-British (FAB) subtype, phenotype, karyotype, and long-term survival. wt1 mRNA was detectable in 124 of 161 (77%) samples at diagnosis and in first relapse. wt1 expression was independent from age, antecedent myelodysplastic syndrome or FAB subtype, with the exception of a significant difference in M5 leukemias showing wt1 transcripts in only 40% (P = .0025). There was no correlation between the level of wt1 mRNA and response to treatment or the prognostic groups defined by the karyotype. Concerning long-term survival, patients with high levels of wt1 had a significantly worse overall survival (OS) than those with not detectable or low levels. The 3-year OS for all newly diagnosed AMLs was 13% and 38% (P = .038), respectively, and 12% and 43% (P = .014) for de novo AMLs. The difference was more distinct in patients less than 60 years of age. During follow-up, all patients achieving complete remission became wt1 negative. Reoccurrence of wt1 transcripts predicted relapse. The data indicate that high expression of wt1 mRNA is associated with a worse long-term prognosis.

Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia

“…(Inoue et al, 1996(Inoue et al, , 1997. Several studies (Brieger et al, 1994;Schmid et al, 1997) using a qualitative assay for WT1 in AML found no correlation between WT1 expression at diagnosis and achievement of CR, whereas Bergmann et al (1997) have shown a tendency towards a higher CR rate in patients with low-level expression of WT1 mRNA using a semiquantitative technique. However, Inoue et al (1996) showed a clear inverse correlation between high WT1 levels in AL and prognosis in terms of CR, DFS and OS.…”

Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia

“…In recent years, several studies reported an overexpression of WT1 in various hematological malignancies, including AML where WT1 is highly expressed at diagnosis in about 80-90% of cases (1)(2)(3)(4)(5)(6). Moreover, it is now evident that WT1 values correlate with disease status, thus being a good candidate for the evaluation of MRD during and after treatment, especially in the relevant percentage of patients who lack a specific molecular marker of their disease (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The aim of the present study was to explore if the WT1 quantitative expression evaluation may be a useful marker of MRD in patients with AML after reduced-intensity conditioning (RIC)-SCT.…”

Fluorescent 5′‐exonuclease assay for the absolute quantification of Wilms' tumour gene (WT1) mRNA: implications for monitoring human leukaemias

“…Studies investigating the clinical value of WT1 RNA detection produced conflicting results. While few investigators draw a clear correlation between strong WT1 expression at initial diagnosis and poor prognosis (Inoue et al, 1994;Bergmann et al, 1997), others could not confirm these findings (Schmid et al, 1997).…”