A GATA-2/estrogen receptor chimera functions as a ligand-dependent negative regulator of self-renewal

被引:75
作者
Heyworth, C
Gale, K
Dexter, M
May, G
Enver, T [1 ]
机构
[1] Inst Canc Res, Chester Beatty Labs, Sect Gene Funct & Regulat, London SW3 6JB, England
[2] Christie Hosp NHS Trust, Paterson Inst Canc Res, Canc Res Campaign, Sect Hematopoiet Cell & Gene Therapeut, Manchester M20 4BX, Lancs, England
[3] Wellcome Trust Res Labs, London NW1 2BE, England
基金
英国惠康基金;
关键词
stem cells; lineage commitment; interleukin-3; erythropoiesis; myelopoiesis;
D O I
10.1101/gad.13.14.1847
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is functionally implicated in their survival and proliferation. We have used estrogen and tamoxifen-inducible forms of GATA-2 to modulate the levels of GATA-2 in the IL-3-dependent multipotential hematopoietic progenitor cell model FDCP mix. Ligand-dependent induction of exogenous GATA-2 activity did not rescue cells deprived of IL-3 from apoptosis. However, induction of GATA-2 activity in cells cultured in IL-3 blocked factor-dependent self-renewal but not factor-dependent survival: Cells undergo cell cycle arrest and cease proliferating but do not apoptose. This was accompanied by differentiation down the monocytic and granulocytic pathways. Differentiation occurred in the presence of IL-3 and did not require addition of exogenous differentiation growth factors such as G-CSF or GM-CSF normally required to induce granulomonocytic differentiation of FDCP-mix cells. Conversely, EPO-dependent erythroid differentiation was inhibited by GATA-2 activation. These biological effects were obtained with levels of exogenous GATA-2 representing less than twofold increases over endogenous GATA-2 levels and were not observed in cells overexpressing GATA-1/ER. Similar effects on proliferation and differentiation were also observed in primary progenitor cells, freshly isolated from murine bone marrow and transduced with a GATA-2/ER-containing retrovirus. Taken together, these data suggest that threshold activities of GATA-2 in hematopoietic progenitor cells are a critical determinant in influencing self-renewal versus differentiation outcomes.
引用
收藏
页码:1847 / 1860
页数:14
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