Erythroid progenitor renewal versus differentiation: genetic evidence for cell autonomous, essential functions of EpoR, Stat5 and the GR.
Erythroid progenitor renewal versus differentiation: genetic evidence for cell autonomous, essential functions of EpoR, Stat5 and the GR.
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DOI：
10.1038/sj.onc.1209308
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发表时间：
2006-05-11
期刊：
影响因子：
8
通讯作者：
Muellner, E. W.
中科院分区：
文献类型：
--
作者：
Dolznig, H.;Grebien, F.;Deiner, E. M.;Stangl, K.;Kolbus, A.;Habermann, B.;Kerenyi, M. A.;Kieslinger, M.;Moriggl, R.;Beug, H.;Muellner, E. W.
关键词：
造血祖细胞承诺和自我更新与分化之间的平衡由多种转录调节因子与细胞因子受体共同控制。这种平衡的破坏在白血病的发展中越来越被认为是重要的，因为它会导致增强的更新和分化停滞。我们研究了原代小鼠红系祖细胞的更新和分化的调节，这些祖细胞需要促红细胞生成素受体(EPOR)、受体酪氨酸激酶c-Kit和转录调节因子(糖皮质激素受体(GR))的协同作用才能持续更新。然而，GR-(GRdim/DIM)、EpoR-(EpoRH)或STAT5ab功能缺陷(Stat5ab−/−)的小鼠在体内没有表现出严重的红细胞生成缺陷。利用这些突变体的原代红细胞培养，我们提出了功能性GR、EPOR和STAT5对红细胞体外更新至关重要的遗传学证据。GRdim/DIM、EpoRH和Stat5ab−/−小鼠的细胞分化增强而不是更新，导致成熟细胞的积累和逐渐的增殖停滞。促红细胞生成素诱导的终末分化还需要Stat5ab：分化中的Stat5ab−/−红细胞发生了凋亡，而不是红细胞成熟，这是因为没有诱导抗凋亡蛋白Bclxl。外源性bc l-xl可完全修复这种缺陷。这些数据表明，驱动白血病增殖的信号分子也可能对正常红系祖细胞的长期自我更新至关重要。
The balance between hematopoietic progenitor commitment and self-renewal versus differentiation is controlled by various transcriptional regulators cooperating with cytokine receptors. Disruption of this balance is increasingly recognized as important in the development of leukemia,by causing enhanced renewal and differentiation arrest. We studied regulation of renewal versus differentiation in primary murine erythroid progenitors that require cooperation of erythropoietin receptor (EpoR),the receptor tyrosine kinase c-Kit and a transcriptional regulator (glucocorticoid receptor (GR)) for sustained renewal. However, mice defective for GR- (GRdim/dim), EpoR- (EpoRH) or STAT5ab function (Stat5ab−/−) show no severe erythropoiesis defects in vivo. Using primary erythroblast cultures from these mutants, we present genetic evidence that functional GR, EpoR, and Stat5 are essential for erythroblast renewal in vitro. Cells from GRdim/dim, EpoRH, and Stat5ab−/− mice showed enhanced differentiation instead of renewal, causing accumulation of mature cells and gradual proliferation arrest. Stat5ab was additionally required for Epo-induced terminal differentiation: differentiating Stat5ab−/− erythroblasts underwent apoptosis instead of erythrocyte maturation, due to absent induction of the antiapoptotic protein Bcl-XL. This defect could be fully rescued by exogenous Bcl-XL. These data suggest that signaling molecules driving leukemic proliferation may also be essential for prolonged self-renewal of normal erythroid progenitors.
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