Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation
Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation
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白血病骨髓浸润揭示了 Egr3 作为正常造血干细胞增殖的有效抑制剂的新作用
DOI：
10.1182/blood-2015-01-623645
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发表时间：
2015-09-10
期刊：
影响因子：
20.3
通讯作者：
Cheng, Tao
中科院分区：
文献类型：
--
作者：
Cheng, Hui;Hao, Sha;Cheng, Tao
由造血祖细胞生成正常血细胞受损所引起的血细胞减少症是白血病患者发病率和死亡率的重要因素。然而，正常造血细胞被新生的白血病细胞取代的过程以及不同亚群的造血干细胞(HSCs)和造血祖细胞(HPC)在白血病细胞渗透过程中是如何受到明显影响的，目前还知之甚少。为了研究这些重要的问题，我们使用了一个健壮的人MLL-AF9白血病小鼠模型来检测体内白血病细胞扩增过程中HSCs和HPC的抑制情况。在所有的造血亚群中，长期再生的HSCs减少最少，而巨核红系祖细胞的抑制最明显。值得注意的是，几乎所有的造血干细胞在白血病晚期被迫进入非循环状态，但在移植到非白血病宿主后，它们的重建潜力似乎是完整的。基因表达谱和进一步的功能验证表明，Egr3是HSCs增殖潜力的一个强有力的限制因素。因此，本研究不仅为HSCs在白血病中更加紧凑的静止状态提供了分子基础，而且为确定HSCs在疾病中的功能调控提供了新的途径。
Cytopenias resulting from the impaired generation of normal blood cells from hematopoietic precursors are important contributors to morbidity and mortality in patients with leukemia. However, the process by which normal hematopoietic cells are overtaken by emerging leukemia cells and how different subsets of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are distinctly influenced during leukemic cell infiltration is poorly understood. To investigate these important questions, we used a robust non-irradiated mouse model of human MLL-AF9 leukemia to examine the suppression of HSCs and HPCs during leukemia cell expansion in vivo. Among all the hematopoietic subsets, long-term repopulating HSCs were the least reduced, whereas megakaryocytic-erythroid progenitors were the most significantly suppressed. Notably, nearly all of the HSCs were forced into a noncycling state in leukemic marrow at late stages, but their reconstitution potential appeared to be intact upon transplantation into nonleukemic hosts. Gene expression profiling and further functional validation revealed that Egr3 was a strong limiting factor for the proliferative potential of HSCs. Therefore, this study provides not only a molecular basis for the more tightened quiescence of HSCs in leukemia, but also a novel approach for defining functional regulators of HSCs in disease.