Author/Authors :
Ishida، نويسنده , , Daisuke and Kometani، نويسنده , , Kohei and Yang، نويسنده , , Hailin and Kakugawa، نويسنده , , Kiyokazu and Masuda، نويسنده , , Kyoko and Iwai، نويسنده , , Kazuhiro and Suzuki، نويسنده , , Misao and Itohara، نويسنده , , Shigeyoshi and Nakahata، نويسنده , , Tatsutoshi and Hiai، نويسنده , , Hiroshi and Kawamoto، نويسنده , , Hiroshi and Hattori، نويسنده , , Masakazu and Minato، نويسنده , , Nagahiro، نويسنده ,
Abstract :
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.
