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）编码与造血相关的转录因子复合物PEBP2（CBF）的DNA结合子，这是人类白血病相关基因畸变的最常见靶标。我们通过使用靶向基因的实验研究了AML1扮演的作用的分子机制，以及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，AML1支持确定造血的生物学活性取决于其反式激活活性，并且其最多的C末端反式压抑域是可以通过体内造血性造血救援实验来支配的。2。与AML1B同工型相比，我们新地克隆了编码AML1C同工型的cDNA，该cDNA在AML1基因基因座的不同启动子的控制下以不同的方式表达，其表达受代理启动子的调节。 AML1B普遍表达，AML1C的表达似乎与确定的造血症更紧密相关，并且取决于活性AML1基因基因座的存在。3。我们分析了小鼠胚胎干细胞克隆的命运，该克隆在嵌合小鼠内携带敲入AML1-MTG8白血病基因，并发现敲入克隆可能有助于成年小鼠的造血组织。但是，他们从未在特定的无病因的气氛中发展出明显的白血病，这表明这种嵌合白血病基因是必要的，但对于白血病生成不足。我们目前正在产生携带白血病相关点突变（s）AML1基因的种系敲门小鼠，以进一步定义了该基因贡献了该基因贡献了含有leukem的贡献。