Functional analysis of the Wilms' tumor suppressor gene WT1 in hematopoiesis.

Wilms 抑癌基因 WT1 在造血中的功能分析。

• 批准号: 08671216
• 负责人: MIYAGAWA Kiyoshi
• 金额: $ 1.41万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671216/
• 关键词: Transcription factor; Leukemia; Tmuor suppressor gene; Wilms' tumor; がん抑制遺伝子; 骨髄異形成症候群; 染色体転座

Since the Wilms' tumor suppressor gene WTI is expressed in CD34-positive blood stem cells and leukemia, it is probable that WT1 is involved in leukemogenesis. To investigate if WT1 plays a role in leukemogenesis, we screend the WT1 gene from 20 cases of childhood acute myeloid leukemia for structural abnormality. SSCP analysis revealed band shifts suggesting the presence of mutations in three cases. Mutations were confirmed by direct sequencing. A His to Glin substitution at codon 397 was found in acute megakaryoblastic leukemia developed in a patient of the Down syndrome. A His to Leu substitution at codon 405 and an Arg to Gln at codon 394 were found in two cases of acute myeloid leukemia respectively. Thus WT1 mutations were found in 15% of acute myeloid leukemia. These mutations occurred in Zn finger domains, which are important for transcriptional regultion. All the cases carrying WT1 mutations exhibited a poor prognosis, one of which possessed the WT1 mutation at relapse but not at diagnosis. The chromosome translocation t (8 ; 21) was also found in a case with the WT1 mutation. These data strongly suggest that mutations in Zn finger domains of the WT1 gene are associated with the progression of acute myeloid leukemia.

由于Wilms肿瘤抑制基因WTI在cd34阳性造血干细胞和白血病中表达，因此WT1可能参与了白血病的发生。为了研究WT1是否在白血病发生中起作用，我们从20例儿童急性髓性白血病中筛选了WT1基因的结构异常。SSCP分析显示三个病例中存在突变的条带移位。突变通过直接测序证实。在唐氏综合征患者发生的急性巨核母细胞白血病中发现了密码子397处的His与Glin替换。在2例急性髓系白血病中分别发现了密码子405处的His与Leu的替换和密码子394处的Arg与Gln的替换。因此，在15%的急性髓性白血病中发现了WT1突变。这些突变发生在锌指结构域，这对转录调控很重要。所有携带WT1突变的病例预后均较差，其中1例复发时携带WT1突变，但诊断时未携带WT1突变。染色体易位t（8; 21）也见于WT1突变病例。这些数据有力地表明，WT1基因Zn指结构域的突变与急性髓系白血病的进展有关。

项目成果

Hosoya, N.: "Frameshift mutations of the hMSH6 gene in human leukemia cell lines." Japanese Journal of Cancer Research. 89 (1). 33-39 (1998)

Hosoya, N.：“人类白血病细胞系中 hMSH6 基因的移码突变。”

Sugimoto, K.: "Decreased or altered expression of the FHIT gene in human leukemia" Stem Cells. 15-3. 223-228 (1997)

Sugimoto, K.：“人类白血病中 FHIT 基因的表达降低或改变”干细胞。

Ueno H.: "The phosphatidylinositol 3'kinase pathway is required for the survival signal of leukocyte tyrosine kinase." Oncogene. 14. 3067-3072 (1997)

Ueno H.：“磷脂酰肌醇 3 激酶途径是白细胞酪氨酸激酶的生存信号所必需的。”

Sugimoto, K.: "Decreased or altered expression of the FHIT gene in human leukemias" Stem Cells. 15 (3). 223-228 (1997)

Sugimoto, K.：“人类白血病中 FHIT 基因的表达降低或改变”干细胞。

Mitani, K.: "No concomitant occurrence of the N-ras and p53 gene mutations in myelodysplastic syndromes." Leukemia. 11. 863-865 (1997)

Mitani, K.：“骨髓增生异常综合征中 N-ras 和 p53 基因突变不会同时发生。”