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

抑癌基因WT1在人类白血病发生中的作用分析。

基本信息

批准号：
09470230
负责人：
SUGIYAMA Haruo
金额：
$ 7.81万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470230/
关键词：
WT1 tumor suppressor gene oncogene 32D cells hematopoietic progenitor cells WT1遺伝子 Stat3 leukemogenesis G_2 M期

项目摘要

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.

肾母细胞瘤基因WT 1被鉴定为负责肾母细胞瘤（一种儿童肾脏肿瘤）的基因，并被归类为肿瘤抑制基因。编码锌指转录因子的WT 1基因抑制生长因子、β生长因子受体和其他一些基因的转录。我们已经报道了高水平的野生型WT 1表达在新鲜的白血病细胞，无论类型的白血病。WT 1反义寡聚体能特异性抑制白血病细胞的生长。这些结果提出了一个假设，野生型WT 1基因发挥致癌，而不是肿瘤抑制基因的造血祖细胞的功能，并在白血病的发生中起着重要作用。为了证明这一假设，进行了一系列实验。32 D c13是一种白细胞介素3依赖的髓系祖细胞系，在G-CSF的刺激下可分化为成熟的中性粒细胞，而野生型WT 1基因转染后，32 D c13细胞在G-CSF的刺激下可停止分化并继续增殖，同时，32 D c13细胞的CFU-GM、CFU-G、在G-CSF刺激下，WP 1感染的骨髓细胞比对照骨髓细胞形成CFU-M集落，这些结果支持了我们的假设。