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

由于Wilms的肿瘤抑制基因WTI在CD34阳性的血液干细胞和白血病中都有表达，因此WT1可能参与了白血病的发生。为了探讨WT1基因在白血病发生中的作用，我们对20例儿童急性髓系白血病患者的WT1基因进行了结构异常筛查。SSCP分析显示，三个病例的条带发生了移动，表明存在突变。突变通过直接测序得到确认。在1例唐氏综合征患者发生的急性巨核细胞白血病中发现了密码子397的His到Glin替换。在2例急性髓系白血病患者中，分别发现了密码子405的His到Leu和密码子394的Arg到Gln。因此，在15%的急性髓系白血病中发现了WT1突变。这些突变发生在锌指结构域上，这些结构域对转录调控非常重要。所有携带WT1突变的病例预后都很差，其中一例在复发时有WT1突变，但在诊断时没有。1例WT1突变患者还发现t(8；21)易位。这些数据有力地表明WT1基因锌指域的突变与急性髓系白血病的进展有关。

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.