TY - JOUR
T1 - Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice
AU - Ishida, Daisuke
AU - Kometani, Kohei
AU - Yang, Hailin
AU - Kakugawa, Kiyokazu
AU - Masuda, Kyoko
AU - Iwai, Kazuhiro
AU - Suzuki, Misao
AU - Itohara, Shigeyoshi
AU - Nakahata, Tatsutoshi
AU - Hiai, Hiroshi
AU - Kawamoto, Hiroshi
AU - Hattori, Masakazu
AU - Minato, Nagahiro
N1 - Funding Information:
We would like to thank Drs. T. Era and T. Nakano for helpful discussion. This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Culture, Sports, and Technology, Japanese Government.
PY - 2003/7/1
Y1 - 2003/7/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S1535-6108(03)00163-6
DO - 10.1016/S1535-6108(03)00163-6
M3 - Article
C2 - 12892713
AN - SCOPUS:10744228326
SN - 1535-6108
VL - 4
SP - 55
EP - 65
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -