Constitutive Activation of NF-κB Pathway in Hematopoietic Stem Cells Causes Loss of Quiescence and Deregulated Transcription Factor Networks.
Constitutive Activation of NF-κB Pathway in Hematopoietic Stem Cells Causes Loss of Quiescence and Deregulated Transcription Factor Networks.
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DOI：
10.3389/fcell.2018.00143
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发表时间：
2018
影响因子：
5.5
通讯作者：
Rathinam CV
中科院分区：
文献类型：
--
作者：
Nakagawa MM;Chen H;Rathinam CV
确定调节造血干细胞（HSC）功能的特定信号通路的生理作用可能会导致血液疾病的新治疗策略和治疗干预。在这里，我们提供了遗传证据，证明造血干细胞中NF-κB的组成性激活导致造血干细胞池大小减小，再生能力和静止。全球转录谱和生物信息学研究发现，在NF-κB激活失调的造血干细胞中，“干性”和“静止”特征的丧失。特别是，基因集富集分析发现细胞周期蛋白依赖性激酶- Ccnd1上调，细胞周期蛋白依赖性激酶抑制剂p57kip2下调。有趣的是，NF-κB的组成性激活足以改变对HSC自我更新和功能至关重要的转录因子（tf）的调控回路。分子研究发现Junb是造血细胞中NF-κB的直接靶点之一。本质上，这些研究表明，NF-κB信号的异常激活会损害HSC的静止和功能，并改变HSC中的“TF网络”。
Identifying physiological roles of specific signaling pathways that regulate hematopoietic stem cell (HSC) functions may lead to new treatment strategies and therapeutic interventions for hematologic disorders. Here, we provide genetic evidence that constitutive activation of NF-κB in HSCs results in reduced pool size, repopulation capacities, and quiescence of HSCs. Global transcriptional profiling and bioinformatics studies identified loss of ‘stemness’ and ‘quiescence’ signatures in HSCs with deregulated NF-κB activation. In particular, gene set enrichment analysis identified upregulation of cyclin dependent kinase- Ccnd1 and down regulation of cyclin dependent kinase inhibitor p57kip2. Interestingly, constitutive activation of NF-κB is sufficient to alter the regulatory circuits of transcription factors (TFs) that are critical to HSC self-renewal and functions. Molecular studies identified Junb, as one of the direct targets of NF-κB in hematopoietic cells. In essence, these studies demonstrate that aberrant activation of NF-κB signals impairs HSC quiescence and functions and alters the ‘TF networks’ in HSCs.