Molecular basis for leukemic transformation caused by chimeric protein involving the transcription factor AML1 (PEBP2aB).

涉及转录因子 AML1 (PEBP2aB) 的嵌合蛋白引起白血病转化的分子基础。

基本信息

批准号：
12671000
负责人：
OKUDA Tsukasa
金额：
$ 2.3万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671000/
关键词：
RUNX1 AML1 AML1-MTG8 ETO leukemia chromosome translocation transcription factor embronic stem (ES) cell

项目摘要

AML1 (PEBP2αB) encodes the DNA-binding subuit for the hematopoiesis-related transcription factor complex, PEBP2 (CBF), which is the most frequent target of the human leukemia-associated gene aberrations. We investigated the molecular mechanism of actions played by AML1 and how its mutations contribute to the development of leukemia, by using gene-targeting experiments. Our results are summarized as follows :1. We established that the biologic activity of AML1 to support the development of definitive hematopoiesis depends on its trans-activating activity and that its most C-terminal trans-repression domain is dispensable for this action by in vivo hematopoietic rescue experiments.2. We newly cloned the CDNA encoding the AML1c isoform, which is differentially expressed under the control of the distal promoter of AML1 gene locus, in contrast to AML1b isoform, whose expression is regulated by the proximal promoter. While AML1b was expressed ubiquitously, the expression of AML1c appeared to be more closely related to the definitive hematopoiesis and is dependent on the presence of active AML1 gene locus.3. We analyzed the fate of the mouse embryonic stem cell clones which carry a knocked-in AML1-MTG8 leukemic gene within the chimeric mice, and found that the knock-in clones could contribute to the hematopoietic tissues of adult mice. However, they never developed overt leukemia so far as they were kept in the specific-pathogen free atmosphere, indicating that this chimeric leukemia gene is necessary but not sufficient for the leukemogenesis.We are currently generating the germline knock-in mice which carry leukemia associated point mutation(s) of AML1 gene to further define how this gene-mutation contribute to the leukemogenesis.

AML1 (PEBP2αB) 编码造血相关转录因子复合物 PEBP2 (CBF) 的 DNA 结合亚基，PEBP2 (CBF) 是人类白血病相关基因畸变最常见的靶标。通过使用基因靶向实验，其突变如何促进白血病的发展，我们的结果总结如下：1.我们确定了AML1支持该发展的生物活性。确定性造血的作用取决于其反式激活活性，并且通过体内造血拯救实验，其最C端的反式抑制结构域对于这种作用是可有可无的。2． AML1 基因座的远端启动子控制，与 AML1b 亚型不同，AML1b 亚型的表达受近端启动子调控。普遍而言，AML1c 的表达似乎与最终造血作用更为密切相关，并且依赖于活性 AML1 基因位点的存在。3. 我们分析了携带 AML1-MTG8 敲入的小鼠胚胎干细胞克隆的命运。研究人员对嵌合小鼠体内的白血病基因进行了研究，发现敲入克隆可以促进成年小鼠的造血组织，但迄今为止，它们从未发展为明显的白血病。保存在无特定病原体的环境中，表明这种嵌合白血病基因对于白血病的发生是必要的，但还不够。我们目前正在培育携带 AML1 基因的白血病相关点突变的种系敲入小鼠，以进一步确定如何这种基因突变有助于白血病的发生。