Reduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells.
Reduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells.
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DOI：
10.1002/stem.2627
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Xie Y;Koch ML;Zhang X;Hamblen MJ;Godinho FJ;Fujiwara Y;Xie H;Klusmann JH;Orkin SH;Li Z
ERG是一种ETS家族转录因子，在人类白血病中经常过表达，被认为是造血干细胞的关键调节因子。然而，ERG如何控制正常的造血，特别是在干细胞和祖细胞水平，以及它如何有助于白血病的发生仍然不完全清楚。使用同源重组，我们产生了Erg敲低等位基因（Ergkd），其中Erg表达可以通过Cre重组酶有条件地恢复。Ergkd/kd动物在E10.5-E11.5时由于内皮细胞和造血细胞的缺陷而死亡，但可以通过Tie 2-Cre介导的Erg在这些细胞中的恢复而被完全拯救。在Ergkd/+小鼠中，Erg剂量减少约40%会通过减少Lin−Sca-1+c-Kit+（LSK）造血干细胞和祖细胞（HSPC）以及巨核细胞祖细胞的数量来干扰胎肝和骨髓造血。通过遗传嵌合体分析，我们发现，Erg恢复HSPCs竞争Ergkd/+ HSPCs的贡献，成人体内造血。这种缺陷部分是由于HSPC的细胞凋亡增加与减少Erg剂量，表型，5-FU诱导的应激造血过程中变得更加激烈。表达分析表明，减少的ERG表达导致的ERG靶基因参与调节HSPCs的生存，包括增加表达的促凋亡调节因子Bcl 2L 11（Bim）和减少表达的Jun. Collectively，我们的数据表明，ERG控制HSPCs的生存，一个属性，可以利用白血病细胞的一个子集的表达变化。Erg缺失损害胎儿造血（A;比例尺= 1 mm）。其在成人中的表达减少导致造血干/祖细胞（HSPC）数量减少（B），部分原因是HSPC的存活受损，特别是在应激造血期间（C; P值：*p ≤ 0.05; *p≤0.005; *p≤0.001）。在分子水平上，HSPC中Erg表达的降低导致Bcl 2111和IGF/胰岛素信号传导相关基因的上调，以及Jun的下调（D）。
ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele (Ergkd) in which Erg expression can be conditionally restored by Cre recombinase. Ergkd/kd animals die at E10.5–E11.5 due to defects in endothelial and hematopoietic cells, but can be completely rescued by Tie2-Cre-mediated restoration of Erg in these cells. In Ergkd/+ mice, ~40% reduction in Erg dosage perturbs both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin−Sca-1+c-Kit+ (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we find that Erg-restored HSPCs outcompete Ergkd/+ HSPCs for contribution to adult hematopoiesis in vivo. This defect is in part due to increased apoptosis of HSPCs with reduced Erg dosage, a phenotype that becomes more drastic during 5-FU-induced stress hematopoiesis. Expression analysis reveals that reduced Erg expression leads to changes in expression of a subset of ERG target genes involved in regulating survival of HSPCs, including increased expression of a pro-apoptotic regulator Bcl2l11 (Bim) and reduced expression of Jun. Collectively, our data demonstrate that ERG controls survival of HSPCs, a property that may be utilized by leukemic cells. Loss of Erg impairs fetal hematopoiesis (A; Scale bars = 1mm). Its reduced expression in adults leads to reduction in hematopoietic stem/progenitor cell (HSPC) number (B), in part due to impaired survival of HSPCs, particularly during stress hematopoiesis (C; P values: *p≤0.05; ***p≤0.005; ****p≤0.001). At the molecular level, reduced Erg expression in HSPCs leads to upregulation of Bcl2l11 and IGF/insulin signaling-related genes, as well as downregulation of Jun (D).
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