Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice
Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice
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DOI：
10.1016/s1535-6108(03)00163-6
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发表时间：
2003-07-01
期刊：
影响因子：
50.3
通讯作者：
Minato, N
中科院分区：
文献类型：
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作者：
Ishida, D;Kometani, K;Minato, N
SPA-1（信号诱导增殖相关基因-1）是造血祖细胞中主要的Rap1 gtpase激活蛋白。spa -1缺陷小鼠出现一系列髓系疾病，类似于人类慢性髓性白血病（CML）的慢性期、原细胞危象、骨髓增生异常综合征和贫血。白血病前spa -1缺陷小鼠骨髓多潜能造血祖细胞选择性扩增，Rap1GTP异常积累。Rap1的一种活性形式的过表达促进了正常造血祖细胞的增殖，而SPA-1的过表达则明显抑制了这种增殖。此外，在缺乏SPA-1的白血病母细胞系中恢复SPA-1基因导致Rap1GTP积累的溶解和体内白血病原性的丧失。这些结果揭示了Rap1在骨髓增生性干细胞疾病中的作用和SPA-1的肿瘤抑制功能。
SPA-1 (signal-induced proliferation-associated gene-1) is a principal Rap1 GTPase-activating protein in hematopoietic progenitors. SPA-1-deficient mice developed a spectrum of myeloid disorders that resembled human chronic myelogenous leukemia (CML) in chronic phase, CML in blast crisis, and myelodysplastic syndrome as well as anemia. Preleukemic SPA-1-deficient mice revealed selective expansion of marrow pluripotential hematopoietic progenitors, which showed abnormal Rap1GTP accumulation. Overexpression of an active form of Rap1 promoted the proliferation of normal hematopoietic progenitors, while SPA-1 overexpression markedly suppressed it. Furthermore, restoring SPA-1 gene in a SPA-1-deficient leukemic blast cell line resulted in the dissolution of Rap1GTP accumulation and concomitant loss of the leukemogenicity in vivo. These results unveiled a role of Rap1 in myeloproliferative stem cell disorders and a tumor suppressor function of SPA-1.