权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular Analysis of Maturation Arrest Mechanism of Myeloid Leukemogenesis

髓系白血病发生成熟阻滞机制的分子分析

基本信息

批准号：
06404039
负责人：
ASANO Shigetaka
金额：
$ 19.52万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

We have been focusing on the molecular analysis of maturation arrest mechanism underlying the myeloid leukemogenesis using myeloid marker genes, cell cycle related genes and trancriptional factor genes. First of all, we have cloned a novel myeloid cell marker gene of GIG-1 (G-CSF inducible gene-1) from G-CSF stimulated leukemia cells from CML patients. The results demonstrated that GIG-1gene was expressed in myeloid lineage cells at the levels of mRNA and protein. This novel gene was paricularly expressed more in matured cells at protein levels. The elecromicroscopic results revealed the microsomal localization of this protein. The expression of this novel gene together with other myeloid specific marker genes of alkaline phosphatase, myeloperoxidase, defensin are very important to analyze the molecular mechanisms of maturation arrest. Second, we tried to analyze the first event which induced the maturation arrest of myeloid cell lineage. Particulary we focused on PEBP2 alpha and PEBP2 beta genes, DNA binding and DNA nonbinding transcriptional regulating genes respectively, forming heterodimers and both of them are considered strongly involoved in leukemogenesis. The embryos of knockout mice of the PEBP2 beta revealed the severe pictures of hematopoiesis including maturation arrest of the myeloid cells. As the defect of PEBP2 a gene was also reported to be strongly involved in the suppressed hematopoiesis in knockout mice, both of these molecules are consiered to be one of the responsible molecule of maturation arrest found in myeloid leukemia. The use of the normal counterpart genes might be useful for some types of myeloid leukemia with the genetic disruptios of PEBP2 alpha or PEBP2 beta. We also studied the roles of othere transcriptional factors including Evi-1 and cell cycle specific molecules for elucidating the roles of these molecules in the maturation arrest of myeloid leukemia cells.

本论文主要从髓系标志基因、细胞周期相关基因和转录因子基因等方面对髓系白血病发生的成熟阻滞机制进行分子生物学研究。首先，我们从粒细胞集落刺激因子（G-CSF）刺激的CML患者白血病细胞中克隆了一个新的髓系细胞标志基因GIG-1（G-CSF诱导基因-1）。结果表明，GIG-1基因在髓系细胞中有mRNA和蛋白水平的表达。该基因在成熟细胞中特异性表达。电镜结果显示该蛋白质的微粒体定位。这一新基因的表达与碱性磷酸酶、髓过氧化物酶、防御素等髓系特异性标志基因的表达对分析成熟阻滞的分子机制具有重要意义。其次，我们试图分析第一个事件，诱导成熟的髓系细胞系的停滞。特别是PEBP 2 α和PEBP 2 β基因，分别是DNA结合和DNA非结合的转录调控基因，形成异二聚体，它们都被认为与白血病的发生密切相关。PEBP 2 β基因敲除小鼠的胚胎显示出严重的造血现象，包括骨髓细胞的成熟停滞。由于PEBP 2a基因的缺陷也被报道强烈参与敲除小鼠中造血抑制，因此这两种分子被认为是在髓性白血病中发现的成熟停滞的负责分子之一。使用正常的对应基因可能对某些类型的PEBP 2 α或PEBP 2 β基因破坏的髓系白血病有用。我们还研究了Evi-1和细胞周期特异性分子等其他转录因子的作用，以阐明这些分子在髓系白血病细胞成熟阻滞中的作用。