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Molecular Mechanism for Chromosomal Translocation in Human Leukmia

人类白血病染色体易位的分子机制

基本信息

批准号：
18390280
负责人：
MIZUTANI Shuki
金额：
$ 11.36万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
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-18390280/
关键词：
ATM siRNA XPA XAB2 Topo II阻害剤 ATM inhibitor CD34 NOG scid 細胞周期チェックポイント DNA損傷

项目摘要

It is well known that Topoisomerase II inhibitor often causes treatment related leukemia in human. We have demonstrated genomic instability such as a deficiency of ATM is involved in chromosomal translocation and leads to leukemia. We have been interested in recapitulating this phenomenon in human cord blood cells. For this purpose we have successfully constructed renti-virus siRNA system for human ATM, enabling us to proceed this project to further step. We have also conducted a study on how often the human cord blood cells have aberrant clones with regard to gene expression of differentiation-associated markers. In 28 cords blood samples we have identified 9 samples have an apparent abnormal clones. Among 9 samples 5 were characterized by the expression of CD34+CD7+CD45w+, while 4 were by CD34+CD20+CD45+. The clones with CD34+CD7+CD45w+ were recently shown to correspond to precursor NK cells. We are now in the process on the molecular and cytogenetical characterization of these abnormal clones.We have recently identified XAB2 as a co repressor protein. When cells express high amount of XAB2, cells became resistant to differentiation induction by Retinoic Acid. This is a novel molecule which is involved in the maintenance of immaturity of hemopoietic stem cells and we speculate this protein is also involved the chromosomal translocation of hemopoietic stem cells.

拓扑异构酶II抑制剂常导致人类治疗相关性白血病。我们已经证明了基因组的不稳定性，如ATM的缺陷涉及染色体易位，并导致白血病。我们一直有兴趣在人类脐带血细胞中重现这一现象。为此，我们成功地构建了针对人ATM的慢病毒siRNA系统，使我们的项目得以进一步开展。我们还进行了一项关于人类脐带血细胞在分化相关标志物的基因表达方面具有异常克隆的频率的研究。在28份脐带血标本中，我们鉴定出9份标本有明显的异常克隆。9例中5例为CD34+CD7+CD45w+，4例为CD34+CD20+CD45+。最近显示具有CD34+CD7+CD45w+的克隆对应于前体NK细胞。我们现在正在对这些异常克隆进行分子和细胞遗传学鉴定，最近我们已经确定XAB 2是一种辅助阻遏蛋白。当细胞表达高量的XAB 2时，细胞变得抵抗视黄酸的分化诱导。这是一个新的分子，它参与维持造血干细胞的不成熟，我们推测这种蛋白质也参与造血干细胞的染色体易位。