Ishida Daisuke, Kometani Kohei, Yang Hailin, Kakugawa Kiyokazu, Masuda Kyoko, Iwai Kazuhiro, Suzuki Misao, Itohara Shigeyoshi, Nakahata Tatsutoshi, Hiai Hiroshi, Kawamoto Hiroshi, Hattori Masakazu, Minato Nagahiro
Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, 606-8501, Kyoto, Japan.
Cancer Cell. 2003 Jul;4(1):55-65. doi: 10.1016/s1535-6108(03)00163-6.
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.
SPA-1（信号诱导增殖相关基因-1）是造血祖细胞中主要的Rap1 GTP酶激活蛋白。SPA-1基因缺陷型小鼠出现了一系列髓系疾病，类似于人类慢性期慢性粒细胞白血病（CML）、急变期CML、骨髓增生异常综合征以及贫血。白血病前期的SPA-1基因缺陷型小鼠显示出骨髓多能造血祖细胞的选择性扩增，这些祖细胞表现出异常的Rap1GTP积累。活性形式的Rap1过表达促进了正常造血祖细胞的增殖，而SPA-1过表达则明显抑制了这种增殖。此外，在SPA-1基因缺陷的白血病母细胞系中恢复SPA-1基因导致Rap1GTP积累的消散以及体内白血病致瘤性的随之丧失。这些结果揭示了Rap1在骨髓增殖性干细胞疾病中的作用以及SPA-1的肿瘤抑制功能。
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