High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome.

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.

[1]  H. Koeffler,et al.  Expression of the candidate Wilm's tumor gene, WT1, in human leukemia cells. , 1993, Leukemia.

[2]  P. Berry,et al.  Inactivation of the remaining allele of the WT1 gene in a Wilms' tumour from a WAGR patient. , 1992, Oncogene.

[3]  U. Maurer,et al.  Wilms tumor gene expression in acute myeloid leukemias. , 1997, Leukemia & lymphoma.

[4]  Henry A. Erlich,et al.  Enzymatic amplification of ?-globin genomic sequences and restriction site analysis for diagnosis of , 1985 .

[5]  D. Hogge.  Cytogenetics and oncogenes in leukemia. , 1994, Current opinion in oncology.

[6]  J. Licht,et al.  The WT1 Wilms' tumor suppressor gene: how much do we really know? , 1996, Biochimica et biophysica acta.

[7]  K. Mullis,et al.  Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. , 1988, Science.

[8]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[9]  David Housman,et al.  WT-1 is required for early kidney development , 1993, Cell.

[10]  Z. Wang,et al.  The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains. , 1993, The Journal of biological chemistry.

[11]  E. Thiel,et al.  Expression of the WT1 Wilms' tumor gene by normal and malignant human melanocytes , 1994, International journal of cancer.

[12]  N. Mantel.  Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[13]  D. Housman,et al.  Alternative splicing and genomic structure of the Wilms tumor gene WT1. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D. Haber,et al.  WT1: a novel tumor suppressor gene inactivated in Wilms' tumor. , 1992, The New biologist.

[15]  G. Saunders,et al.  Expression of the Wilms' tumor gene (WT1) in human leukemias. , 1992, Leukemia.

[16]  X. Xia,et al.  Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms' tumor locus. , 1993, The Journal of biological chemistry.