Wilms' tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance.
In a previous study of acute leukemia, we have shown that WT1 gene mutations occur in both myeloid and biphenotypic subtypes, where they are associated with refractoriness to standard induction chemotherapy. We have now extended this study to a total of 67 cases (34 acute myeloid leukemia [AML], 23 acute lymphoblastic leukemia [ALL], 10 acute undifferentiated leukemia [AUL]/biphenotypic) and find that WT1 mutations occur in 14% of AML and 20% of biphenotypic leukemia, but are rare in ALL (one case). In contrast to the findings in Wilms' tumor, where mutations in the WT1 gene usually behave according to Knudson's two hit model for tumor suppressor genes, seven of eight leukemia-associated WT1 mutations are heterozygous, implying a dominant or dominant-negative mode of action in hematopoietic cells. In AML, the presence of a WT1 mutation is associated with failure to achieve complete remission and a lower survival rate. These data (1) confirm that WT1 mutations underlie a similar proportion of cases of AML to that seen in Wilms' tumors and (2) show for the first time that WT1 mutations can contribute to leukemogenesis of lymphoid as well as myeloid origin, suggesting that its normal role in hematopoiesis lies at a very early progenitor stage. The relationship of WT1 mutation to chemoresistance merits further investigation.
King-Underwood
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Section of Paediatric Oncology, Institute of Cancer Research, Belmont, Sutton, Surrey, UK. kpj@icr.ac.uk
Pritchard-Jones
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D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016162:Genes, Wilms Tumor; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*; D025721:WT1 Proteins
D004268:DNA-Binding Proteins; D014157:Transcription Factors; D025721:WT1 Proteins