Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors
Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors
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DOI：
10.1182/blood-2002-06-1774
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发表时间：
2003-02-01
期刊：
影响因子：
20.3
通讯作者：
Hellstrom-Lindberg, E
中科院分区：
文献类型：
--
作者：
Tehranchi, R;Fadeel, B;Hellstrom-Lindberg, E
低危骨髓增生异常综合征(MDS)包括难治性贫血和铁粒母细胞贫血，其特征是红系祖细胞凋亡性死亡增加。然而，在MDS中导致这种病理性细胞死亡的信号通路仍然不清楚。促红细胞生成素联合粒细胞集落刺激因子(G-CSF)治疗可协同改善MDS患者的贫血，并伴随着骨髓前体细胞凋亡的减少。此外，我们以前报道过G-CSF抑制Fas诱导的铁粒母细胞贫血(RARS)中caspase的激活。目前的数据显示，几乎50%来自MDS患者的红系祖细胞自发地从线粒体中释放细胞色素c，随后激活caspase-9，而正常的红系祖细胞则没有这两个特征。G-CSF显著抑制细胞色素c的释放和抑制细胞凋亡，尤其是在铁粒母细胞性贫血患者的细胞中。此外，在所有低危MDS病例中，抑制caspase-9均抑制了红系祖细胞的自发和Fas介导的凋亡。我们认为MDS前体细胞对死亡受体刺激的敏感性增加是由于这些细胞中凋亡信号通路的线粒体轴的结构性激活。这些研究从机制上解释了生长因子对MDS患者的有益临床效果，并为其他骨髓疾病中生长因子介导的抑制细胞凋亡的研究提供了一个模型。(C)2003年，由美国血液病学会提供。
Low-risk myelodysplastic syndromes (MDS), including refractory anemia and sideroblastic anemia, are characterized by increased apoptotic death of erythroid progenitors. The signaling pathways that elicit this pathologic cell death in MDS have, however, remained unclear. Treatment with erythropoietin in combination with granulocyte colony-stimulating factor (G-CSF) may synergistically improve the anemia in patients with MDS, with a concomitant decrease in the number of apoptotic bone marrow precursors. Moreover, we have previously reported that G-CSF inhibits Fas-induced caspase activation in sideroblastic anemia (RARS). The present data demonstrate that almost 50% of erythroid progenitor cells derived from patients with MDS exhibit spontaneous release of cytochrome c from mitochondria with ensuing activation of caspase-9, whereas normal erythroid progenitors display neither of these features. G-CSF significantly inhibited cytochrome c release and suppressed apoptosis, most noticeably in cells from patients with sideroblastic anemia. Furthermore, inhibition of caspase-9 suppressed both spontaneous and Fas-mediated apoptosis of erythroid progenitors in all low-risk MDS cases studied. We propose that the increased sensitivity of MDS progenitor cells to death receptor stimulation is due to a constitutive activation of the mitochondrial axis of the apoptotic signaling pathway in these cells. These studies yield a mechanistic explanation for the beneficial clinical effects of growth factor administration in patients with MDS, and provide a model for the study of growth factor-mediated suppression of apoptosis in other bone marrow disorders. (C) 2003 by The American Society of Hematology.