Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis
Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis
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DOI：
10.1084/jem.20042541
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发表时间：
2005-07-04
影响因子：
15.3
通讯作者：
Nakauchi, H
中科院分区：
文献类型：
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作者：
Kato, Y;Iwama, A;Nakauchi, H
尽管白血病干细胞系统的概念最近已经被广泛接受，但其本质和潜在的分子机制仍然不清楚。信号转导和转录激活因子3(STAT3)和信号转导与转录激活因子5(STAT5)在各种血液系统肿瘤中经常被检测到。为了评估它们在正常和白血病干细胞中的作用，我们利用构成活性的STAT突变来选择性地激活造血干细胞(HSCs)中的STAT信号。CD34(-)c-Kit(+)SCA-1(+)谱系标志(-)(CD34(-)KSL)中STAT5的激活导致多潜能祖细胞的急剧扩增，并促进HSC在体外的自我更新。与之形成鲜明对比的是，STAT3在体内对HSC的维持是必不可少的，它的激活促进了HSC在体外的谱系承诺。在小鼠骨髓增生性疾病(MPD)模型中，CD34(-)KSL HSCs持续激活STAT5，但在CD34(+)KSL多潜能祖细胞中不能诱导致死性MPD，表明STAT5促进造血干细胞自我更新的能力在MPD的发生发展中起关键作用。我们的发现共同确立了STAT5在正常干细胞和白血病干细胞自我更新中的特殊作用。
Although the concept of a leukemic stem cell system has recently been well accepted, its nature and the underlying molecular mechanisms remain obscure. Constitutive activation of signal transducers and activators of transcription 3 (STAT3) and STAT5 is frequently detected in various hematopoietic tumors. To evaluate their role in normal and leukemic stem cells, we took advantage of constitutively active STAT mutants to activate STAT signaling selectively in hematopoietic stem cells (HSCs). Activation of STAT5 in CD34(-)c-Kit(+)Sca-1(+) lineage marker(-) (CD34(-)KSL) HSCs led to a drastic expansion of multipotential progenitors and promoted HSC self-renewal ex vivo. In sharp contrast, STAT3 was demonstrated to be dispensable for the HSC maintenance in vivo, and its activation facilitated lineage commitment of HSCs in vitro. In a mouse model of myeloproliferative disease (MPD), sustained STAT5 activation in CD34(-)KSL HSCs but not in CD34(+)KSL multipotential progenitors induced fatal MPD, indicating that the capacity of STAT5 to promote self-renewal of hematopoietic stem cells is crucial to MPD development. Our findings collectively establish a specific role for STAT5 in self-renewal of normal as well as leukemic stem cells.