Abnormal hematopoiesis in Gab2 mutant mice

被引:37
作者
Zhang, Yi
Diaz-Flores, Ernesto
Li, Geqiang
Wang, Zhengqi
Kang, Zizhen
Haviernikova, Eleonora
Rowe, Sara
Qu, Cheng-Kui
Tse, William
Shannon, Kevin M.
Bunting, Kevin D.
机构
[1] Case Western Reserve Univ, Sch Med, Dept Med, Div Hematol Oncol, Cleveland, OH 44106 USA
[2] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[4] Program Stem Cell & Regenerat Med, Cleveland, OH USA
关键词
D O I
10.1182/blood-2006-11-060707
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Gab2 is an important adapter molecule for cytokine signaling. Despite its major role in signaling by receptors associated with hematopoiesis, the role of Gab2 in hematopoiesis has not been addressed. We report that despite normal numbers of peripheral blood cells, bone marrow cells, and c-Kit(+)Lin(-)Sca-1(+) (KLS) cells, Gab2-deficient hematopoietic cells are deficient in cytokine responsiveness. Significant reductions in the number of colony-forming units in culture (CFU-C) in the presence of limiting cytokine concentrations were observed, and these defects could be completely corrected by retroviral complementation. In earlier hematopoiesis, Gab2-deficient KLS cells isolated in vitro responded poorly to hematopoietic growth factors, resulting in an up to 11-fold reduction in response to a cocktail of stem cell factor, flt3 ligand, and thrombopoietin. Gab2-deficient c-Kit(+)Lin(-) cells also demonstrate impaired activation of extracellular signal-regulated kinase (ERK) and S6 in response to IL-3, which supports defects in activating the phosphaticlylinositol-3 kinase (PI-3K) and mitogen-associated protein kinase (MAPK) signaling cascades. Associated with the early defects in cytokine response, competitive transplantation of Gab2(-/-) bone marrow cells resulted in defective long-term multilineage repopulation. Therefore, we demonstrate that Gab2 adapter function is intrinsically required for hematopoietic cell response to early-acting cytokines, resulting in defective hematopoiesis in Gab2-deficient mice.
引用
收藏
页码:116 / 124
页数:9
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