Leukemogenic Mechanism by genomic mutations of hematopoietic-speci is transcription factor, AML1/RUNX1

造血特异性基因组突变导致的白血病机制是转录因子 AML1/RUNX1

基本信息

批准号：
18591078
负责人：
OKUDA Tsukasa
金额：
$ 2.57万
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：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591078/
关键词：
cancer leukemia genome-modified mouse transcription factor RUNX1 AML1 retrovirus

项目摘要

Hematopoietic transcription factor AML1 (RUNX1) is a frequent target of leukemia-associated chromosome translocations. AML1 is rearranged by chromosome translocations to form chimera protein which acts as a strong trans-dominant inhibitor against wild-type AML1 and contributes to leukemia development, while mis-sense mutations at DNA-contacting residues of the molecule have also been recognized as leukemia-associated mutations recently. In this study we assessed the consequences of these point mutations in context of entire animal. We successfully introduced each of the mutations, R139Q, R174Q, R177Q, or I150ins, into mouse germline through the knock-in approach. All mouse lines were embryonic lethal when inherited homozygously, indicating that these alleles are all loss-of-function type mutations. In contrast, heterozygotes for each mutation were normally born and developed healthy. They were fertile and developed no overt leukemia through their lives. Thus, these mutations seem to be insufficient to cause clinical leukemia as single allele, showing sharp contrast to the case for human diseases. Thus, it was suggested that additional co-operative mutation (s) are required to develop the disease. In order to address this issue, we performed retroviral-infection experiment using R174Q mice, and found that heterozygotes had tendency to develop leukemia earlier than their wild-type littermates did. This observation indicates that one allele mutation of AML1 serves to promote leukemia-onset one step further. In addition, cloning-analysis for proviral integration sites within the leukemia genome revealed a number of candidate co-operative genes. We are currently analyzing these gene products to see if they collaborate in human diseases.

造血转录因子AML1（RUNX1）是白血病相关染色体易位的常见靶标。 AML1由染色体易位重新排列以形成嵌合蛋白，该蛋白是对野生型AML1的强烈反式抑制剂，并有助于白血病的发育，而该分子的DNA接触残留物的错误 - 敏感突变也被认为是白血病与白血病相关的突变。在这项研究中，我们评估了这些点突变在整个动物背景下的后果。我们通过敲入方法成功地将每个突变，R139Q，R174Q，R177Q或I150INS引入了小鼠种系中。当纯合遗传时，所有小鼠系都是胚胎致死的，表明这些等位基因都是功能丧失型突变。相比之下，每个突变的杂合子通常诞生并发展健康。他们肥沃，一生中没有明显的白血病。因此，这些突变似乎不足以引起临床白血病为单个等位基因，与人类疾病的病例形成了鲜明的对比。因此，有人提出发展疾病需要其他合作突变。为了解决这个问题，我们使用R174Q小鼠进行了逆转录病毒感染实验，并发现杂合子倾向于比其野生型同窝仔的趋势更早发展白血病。该观察结果表明，AML1的一个等位基因突变可促进白血病发作进一步。此外，白血病基因组中前病毒整合位点的克隆 - 分析显示了许多候选合作基因。我们目前正在分析这些基因产品，以查看它们是否在人类疾病中进行合作。