Analysis of roles of tumor suppressor gene WT1 in human leukemogenesis.

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The Wilms' tumor gene WT1 was identified as a gene responsible for Wilms' tumor, a childhood kidney neoplasm and classified as a tumor suppressor gene. The WT1 gene encoding a zinc finger transcription factor represses transcription of growth factors, p growth factor receptors and some other genes. We have reported high levels of wild-type WT1 expression in fresh leukemic cells regardless of the types of leukemias. Furthermore, WT1 antisense oligomer specifically inhibited the growth of leukemia cells. These results have raised a hypothesis that the wild-type WT1 gene exerts an oncogenic rather than a tumor suppressor gene function in hematopoietic progenitor cells and plays an important role in leukemogenesis. To prove this hypothesis, a series of experiments were performed. 32D c13, an interleukin 3-dependent myeloid progenitor cell line, differentiates into mature neutrophils in response to G-CSF.However, when transfected wild-type WT1 gene was constitutively expressed in 32D c13 cells, the cells stopped differentiating and continued to proliferate in response to G-CSF.Furthermore, significantly more CFU-GM, CFU-G, and CFU-M colonies were formed in WP1-infected bone marrow (BM) cells than in control BM cells in response to G-CSF.These results supported our hypothesis.