DOMINANT-NEGATIVE MUTATIONS OF THE WILMS-TUMOR PREDISPOSING GENE (WT1) ARE INFREQUENT IN CML BLAST CRISIS AND DE-NOVO ACUTE-LEUKEMIA

To determine if mutations of the Wilms' tumour predisposing gene (WT1) are associated with haematological malignancies, we have investigated 65 cases of acute leukaemia, including 39 patients in blast crisis of chronic myeloid leukaemia (CML), by amplification of WT1 exons 7, 8 a nd 9 followed by single-strand conformation polymorphism analysis. WT1 transcripts were detected by RT-PCR in all samples. An exon 7 silent polymorphism (A-->G; Arg 313) was identified in 17 individuals, 5 of w hom were homozygous, but no other lesions were found. In 1 sample from a patient with acute lymphoblastic leukaemia a smaller size transcrip t missing exon 9 was detected; a similar abnormality has been describe d previously in a patient with Wilms' tumour and the resultant protein shown to act in a dominant-negative manner. No mutations of the exon 9 donor or acceptor splice sites were found in this patient and the ba sis of the abnormal transcript remains obscure. We conclude that domin ant-negative mutations of the zinc finger region of the WT1 gene are u ncommon in CML blast crisis. Abnormalities of this gene may, however, contribute to a small proportion of cases of de novo acute leukaemia.