Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice.
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.
Ishida
Daisuke
D
Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, 606-8501, Kyoto, Japan.
Kometani
Kohei
K
Yang
Hailin
H
Kakugawa
Kiyokazu
K
Masuda
Kyoko
K
Iwai
Kazuhiro
K
Suzuki
Misao
M
Itohara
Shigeyoshi
S
Nakahata
Tatsutoshi
T
Hiai
Hiroshi
H
Kawamoto
Hiroshi
H
Hattori
Masakazu
M
Minato
Nagahiro
N
D000818:Animals; D001752:Blast Crisis / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D020690:GTPase-Activating Proteins; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D009687:Nuclear Proteins / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C490403:SIPA1 protein, human; C091108:Sipa1 protein, mouse; D020827:rap1 GTP-Binding Proteins