Mutation of the WT1 gene in myelodysplastic syndrome and acute myeloid leukaemia post myelodysplastic syndrome.

Abstract

Myelodysplastic syndrome (MDS) comprises a heterogenous group of haematological disorders that are regarded as preleukaemic stages. Patients with MDS frequently exhibit progressive increases in blast counts in bone marrow, showing a transition to acute myeloid leukaemia (AML) post MDS. Cancer is considered to develop during the acquisition of multiple genetic events responsible for malignant transformation. The WT1 gene was cloned as a candidate of tumour suppressor gene for Wilms tumour (Call et al, 1990). The gene is located at chromosome band 11p13 and allelic loss has been reported within this region in Wilms tumour. The gene encodes a zinc finger transcriptional factor, that either activates or represses transcription. The WT1 gene is mutated in about 10% of patients with Wilms tumour. A mutation of the WT1 gene in leukaemia was first reported in a Wilms tumour survivor with WAGR syndrome (Wilms tumour, aniridia, genitourinary abnormalities, and mental retardation) (Pritchard-Jones et al, 1994). The same group of investigators also reported that WT1 mutations were detected in four of 36 patients with sporadic acute leukaemias. They found that mutations were observed in AML and biphenotypic leukaemia but were rare in acute lymphoblastic leukaemia (King-Underwood & Pritchard-Jones, 1998). Mutations of the WT1 gene may be involved not only in acute leukaemia but also in MDS. We analysed mutations of the WT1 gene in 28 patients with MDS and AML post MDS, using polymerase chain reaction–single-strand conformation polymorphism analysis (PCR-SSCP). PCR-SSCP analysis was performed within exons 7–10, those containing four zinc finger regions of the WT1 gene, since mutations have been reported in these zinc finger regions (Little et al, 1992). Mobility shifts were detected in one patient with AML post MDS. Sequence analysis was subsequently performed, and a missense mutation CGG to TGG, converting Arg to Trp at codon 394 was identified. This mutation was identical to one that was reported as a germ-line mutation in a patient with Denys-Drash syndrome, a triad of genital malformation, nephrotic syndrome, and Wilms tumour (Coppes et al, 1992). Our patient did not have genital malformations or a family history of Denys-Drash syndrome. To test the possibility of a germ-line mutation, an autopsy sample of liver tissue from the same patient was analysed. Normally migrating bands were observed in the sample, indicating the mobility shifts were due to an acquired change. The same mutation was also found in a patient with acute undifferentiated leukaemia (King-Underwood & Prichard-Jones, 1998) and may play a role in the development of these leukaemias.