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

由于Wilms肿瘤抑制基因WTI在CD 34阳性造血干细胞和白血病中表达，因此WT 1可能参与白血病的发生。为探讨WT 1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进行了WT 1基因结构异常的检测。SSCP分析显示，在三个案例中，条带的变化表明突变的存在。通过直接测序确认突变。在唐氏综合征患者发生的急性巨核细胞白血病中发现了397位密码子His到Glin的替换。在2例急性髓系白血病中分别发现405位密码子由His变为Leu，394位密码子由Arg变为Gln。因此，在15%的急性髓系白血病中发现了WT 1突变。这些突变发生在锌指结构域，这是重要的转录调控。所有携带WT 1突变的病例均表现出不良预后，其中1例在复发时携带WT 1突变，但在诊断时未携带。1例WT 1基因突变患者还发现染色体易位t（8 ; 21）。这些数据有力地表明，突变的锌指结构域的WT 1基因与急性髓性白血病的进展。

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.