Analysis of Molecular Mechanism of Blastic Crisis in Chronic Myelocytic Leukemia

慢性粒细胞白血病原始细胞危象的分子机制分析

基本信息

批准号：
07042002
负责人：
HIRAI Hisamaru
金额：
$ 3.65万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1995
资助国家：
日本
起止时间：
1995 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07042002/
关键词：
Chronic Myelocytic Leukemia Blastic Crisis Evi-1 Gene Cell Cycle p16INK4A Gene p53 Gene RB Protein Tumor Suppressor Gene

项目摘要

Evi-1 is a transforming gene originally identified in a common integration site of murine leukemia retrovirus and mapped in human chromosome 3q26. It is overexpressed in retrovirus induced murine myeloid leukemias as well as human myeloid leukemias with 3q26 abnormalities, and thus thought to be responsible for both human and murine leukemogenesis. In this study, a possible involvement of the Evi-1 gene in blastic transformation of chronic myelocytic leukemia (CML) was examined by northern blot analysis, and the frequencies of its expression were compared between Japanese patients and American ones. Expression of the Evi-1 gene was detected in 48% of Japanese patients and 40% of American ones. Our results suggest that increased expression of the Evi-1 gene may play an important role in development of human leukemias, especially in progression from chronic phase to blastic crisis of CML even without 3q26 abnormalities.It is now evident that the cell cycle machinery has a variety of elem … More ents negatively regulating cell cycle progression. Among these negative regulators in cell cycle control, however, only 4 have been shown to be consistently involved in development of human cancers as tumor suppressors : Rb (Retinoblastoma susceptibility protein), p53, and recently identified two cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are functional interrelations among these negative regulators in the cell cycle machinery, it is particularly interesting to investigate the multiplicity of inactivations of these tumor suppressors in blastic transformation of CML.In order to address this point, we examined inactivations of these four genes in patients with blastic crisis of CML by Southern blot and PCR-SSCP analyzes. We also analyzed Rb protein expression by western blot analysis. The p16INK4A was homozygously deleted in 9% and 15% in Japanese patients and American ones. The p53 gene was mutated in 27% and 20%, and the RB protein was inactivated in 18% and 14% in Japanese patients and American ones, respectively. These results suggest that there are no significant differences in inactivation frequences of these tumor suppressors in blastic transformation of CML. Less

EVI-1是一种最初在鼠白血病逆转录病毒的共同整合位点鉴定的转化基因，并在人类3q26染色体中映射。它在逆转录病毒引起的鼠类髓样白血病以及人类髓样白血病中过表达，其异常异常，因此被认为是人类和鼠白血病的原因。在这项研究中，通过North Blot分析检查了EVI-1基因参与慢性脊髓细胞白血病（CML）的爆炸转化，并比较了日本患者和美国患者的表达频率。在48％的日本患者和40％的美国患者中检测到EVI-1基因的表达。我们的结果表明，EVI-1基因的表达增加可能在人类白血病的发展中起重要作用，尤其是在从慢性阶段到爆炸危机CML的发展，即使没有3Q26异常。然而，在细胞周期控制中的这些负调节剂中，只有4个被证明与人类癌的发育始终参与肿瘤补充剂的发展：RB（视网膜母细胞瘤易感性蛋白），p53，最近鉴定出了两个依赖细胞周期蛋白依赖性激酶抑制剂P16INK4A/MTS1/MTS1和P15INK4B/MTS2。由于细胞周期机制中这些负调节剂之间存在功能相互关系，因此研究这些肿瘤补充剂在cml的爆炸转化中的灭绝次是为了解决这一点的灭绝，我们检查了CML爆炸危机中CML危机中的这四个基因的失活，而Southern Blot和PCR-SSCP分析。我们还通过蛋白质印迹分析分析了RB蛋白表达。日本患者和美国患者的P16INK4A在9％和15％中被纯合删除。 p53基因在27％和20％中被突变，而RB蛋白分别在日本患者和美国患者中分别以18％和14％的毒素失活。这些结果表明，在CML的爆炸转化中，这些肿瘤补充剂的灭活频率没有显着差异。较少的