Functional analysis of WT1 mutation in acute myeloid leukemia

急性髓系白血病WT1突变的功能分析

• 批准号: 10670951
• 负责人: MIYAGAWA Kiyoshi
• 金额: $ 2.05万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670951/
• 关键词: WT1; Leukemia; Mutation; ウィルムス腫瘍遺伝子

Wilms' tumor gene WT1 was originally isolated as a tumor suppressor for childhood Wilms' tumor. The gene is expressed in hematopoietic progenitor cells and leukemia. To investigate the role for WT1 in leukemogenesis. we performed mutation analysis in leukemia. WT1 mutation was found in acute myeloid leukemia but not in other types of leukemia. Furthermore. WT1 mutation was associated with poor prognosis, suggesting that WT1 dysfunction may lead to the progression of leukemia.Several lines of evidence suggest that WT1 may be a transcriptional regulator. More than 20 genes have been proposed as transcriptional targets for WT1. We generated ES cells homozygous for WT1 mutation and compared expression pattern between wild-type and double-knockout ES cells using the DNA array technique. We could not detect the change of the expression pattern of the candidate targets for WT1. This finding suggests that the proposed targets may not be transcriptionally regulated by WT1 in vivo. These genes were identified by artificial methods that did not reflect physiological interactions. Since it is well established that WT1 is physically associated splice factors in vivo, it is highly likely that WT1 function is mediated by its, posttranscriptional expression control.

Wilms肿瘤基因WT1最初是作为儿童Wilms肿瘤的肿瘤抑制基因分离的。该基因在造血祖细胞和白血病中表达。探讨WT1在白血病发生中的作用。我们对白血病进行了突变分析WT1突变在急性髓系白血病中发现，而在其他类型白血病中未发现。此外。WT1突变与预后不良有关，提示WT1功能障碍可能导致白血病的进展，多条证据提示WT1可能是一种转录调控因子。已经提出了20多个基因作为WT1的转录靶点。我们产生了WT1突变纯合的ES细胞，并使用DNA阵列技术比较了野生型和双敲除ES细胞之间的表达模式。我们无法检测到WT1候选靶点表达模式的变化。这一发现表明，拟议的目标可能不转录调节WT1在体内。这些基因是通过人工方法鉴定的，不反映生理相互作用。由于WT1在体内与剪接因子物理相关，因此WT1的功能很可能是由其转录后表达调控介导的。

项目成果

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