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A new model mice for human chronic myelogenous leukemia by the disruption of SPA-1 gene.

通过破坏 SPA-1 基因建立人类慢性粒细胞白血病的新模型小鼠。

基本信息

批准号：
15590337
负责人：
HATTORI Masakazu
金额：
$ 2.3万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Rap1 is a member of the Ras family of GTPases and, depending on the cellular context, has an important role in the regulation of proliferation or cell adhesion. In lympho-hematopoietic tissues, SPA-1 is a principal Rap1 GTPase-activating protein. Mice that were deficient for the SPA-1 gene developed age-dependent progression of T-cell immunodeficiency followed by a spectrum of late onset myeloproliferative disorders, mimicking human chronic myeloid leukemia. Deregulated Rap1 activation in SPA-1-deficient mice caused enhanced expansion of the bone marrow hematopoietic progenitors, but induced progressive unresponsiveness or anergy in T cells. Rap1 and its regulator, SPA-1, could, therefore, provide unique molecular targets for the control of human hematologic malignancy.SPA-1-deficiency also caused the age-dependent expansion of B1a cell producing anti-dsDNA and anti-nuclear antibodies in the peritoneal cavity resulting in lupus-like autoimmunity. Sustained Rap1 activation in the bone marrow B cell precursors in SPA-1-deficient mice induced markedly biased Vκ gene repertoire and extensive "partial" receptor editing by activating OcaB gene controlling Vκ gene recombination, thereby leading to the generation of pathogenic self-reactive B1 cells. Furthermore, SPA-1-deficient mice frequently developed leukemia preferentially of B1 cell origin along with hemolytic autoantibody production. The results suggest that antigen-receptor repertoire formation in developing B cells can be significantly modified by the stimuli from bone marrow microenvironment, in which Rap1-signal plays an important role.

RAP1是Ras家族GTP酶家族的成员之一，根据细胞环境的不同，它在细胞增殖或细胞黏附的调节中起着重要的作用。在淋巴造血组织中，SPA-1是主要的Rap1 GTP酶激活蛋白。缺乏SPA-1基因的小鼠出现了T细胞免疫缺陷的年龄依赖性进展，随后出现了一系列迟发性骨髓增生性疾病，类似于人类慢性髓系白血病。在SPA-1缺陷小鼠中，RAP1的失控激活导致骨髓造血祖细胞的扩张增强，但导致T细胞进行性无反应或无能。因此，RAP1及其调节因子SPA-1可以为人类血液系统恶性肿瘤的控制提供独特的分子靶点。SPA-1缺乏还导致B1A细胞的年龄依赖性扩张，产生抗双链DNA和抗核抗体，从而导致狼疮样自身免疫。SPA-1缺陷小鼠骨髓B细胞前体细胞持续激活RAP1，通过激活控制V-κ基因重组的OCAB基因，导致V-κ基因库的明显偏向和广泛的“部分”受体编辑，从而导致致病的自身反应性B1细胞的产生。此外，SPA-1基因缺陷的小鼠经常发生B1细胞起源的白血病，同时产生溶血性自身抗体。结果表明，骨髓微环境对发育中B细胞抗原受体谱系的形成有明显的调节作用，RAP1信号在其中起重要作用。