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

Wilms‘s肿瘤基因WT1被鉴定为与Wilms’s瘤有关的基因，Wilms‘s瘤是一种儿童肾脏肿瘤，被归类为肿瘤抑制基因。编码锌指转录因子的WT1基因抑制生长因子、p生长因子受体和其他一些基因的转录。我们已经报道了在新鲜白血病细胞中野生型WT1的高水平表达，而不考虑白血病的类型。此外，WT1反义寡聚物可特异性抑制白血病细胞的生长。这些结果提出了一种假设，即野生型WT1基因在造血祖细胞中发挥致癌作用，而不是抑癌基因功能，在白血病发生中发挥重要作用。为了证明这一假设，进行了一系列实验。32D c13是一种依赖白介素3的髓系祖细胞，在G-CSF刺激下可分化为成熟的中性粒细胞。但当野生型WT1基因在32D c13细胞中结构性表达时，细胞停止分化并继续增殖。此外，WP1感染的骨髓(BM)细胞在G-CSF作用下形成的CFU-GM、CFU-G和CFU-M集落明显多于对照BM细胞。

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.