Functional analysis of WT1 mutation in acute myeloid leukemia

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Wilms' tumor gene WT1 was originally isolated as a tumor suppressor for childhood Wilms' tumor. The gene is expressed in hematopoietic progenitor cells and leukemia. To investigate the role for WT1 in leukemogenesis. we performed mutation analysis in leukemia. WT1 mutation was found in acute myeloid leukemia but not in other types of leukemia. Furthermore. WT1 mutation was associated with poor prognosis, suggesting that WT1 dysfunction may lead to the progression of leukemia.Several lines of evidence suggest that WT1 may be a transcriptional regulator. More than 20 genes have been proposed as transcriptional targets for WT1. We generated ES cells homozygous for WT1 mutation and compared expression pattern between wild-type and double-knockout ES cells using the DNA array technique. We could not detect the change of the expression pattern of the candidate targets for WT1. This finding suggests that the proposed targets may not be transcriptionally regulated by WT1 in vivo. These genes were identified by artificial methods that did not reflect physiological interactions. Since it is well established that WT1 is physically associated splice factors in vivo, it is highly likely that WT1 function is mediated by its, posttranscriptional expression control.