Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells
Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells
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DOI：
10.1016/j.stem.2008.06.002
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发表时间：
2008-08-07
期刊：
影响因子：
23.9
通讯作者：
Kurokawa, Mineo
中科院分区：
文献类型：
--
作者：
Goyama, Susumu;Yamamoto, Go;Kurokawa, Mineo
Evi-1被认为是与小鼠和人髓性白血病相关的主要癌基因之一。在这里，我们表明，造血干细胞（HSC）在Evi-1缺陷的胚胎数量严重减少，有缺陷的增殖和再生能力。选择性切除Tie 2（+）细胞中的EVIL 1模拟Evi-1缺陷，表明Evi-1功能在Tie 2（+）造血干/祖细胞中是必需的。在成人造血系统中Evi-1的条件性缺失揭示了Evi-1缺陷的骨髓HSC不能维持造血并且失去其再增殖能力。相比之下，Evi-1是血细胞谱系定型的关键。Evi-1（+/-）小鼠表现出HSC活性的中间表型，表明Evi-1的基因剂量要求。我们进一步证明，Evi-1在转化的白血病细胞中的破坏导致其在体外和体内的增殖活性的显着损失。因此，Evi-1是胚胎/成人HSC和转化的白血病细胞增殖所必需的常见和关键调节因子。
Evi-1 has been recognized as one of the dominant oncogenes associated with murine and human myeloid leukemia. Here, we show that hematopoietic stem cells (HSCs) in Evi-1-deficient embryos are severely reduced in number with defective proliferative and repopulating capacity. Selective ablation of EVIL 1 in Tie2(+) cells mimics Evi-1 deficiency, suggesting that Evi-1 function is required in Tie2(+) hemtopoietic stem/progenitors. Conditional deletion of Evi-1 in the adult hematopoietic system revealed that Evi-1-deficient bone marrow HSCs cannot maintain hematopoiesis and lose their repopulating ability. In contrast, Evi-1 is dispensable for blood cell lineage commitment. Evi-1(+/-) mice exhibit the intermediate phenotype for HSC activity, suggesting a gene dosage requirement for Evi-1. We further demonstrate that disruption of Evi-1 in transformed leukemic cells leads to significant loss of their proliferative activity both in vitro and in vivo. Thus, Evi-1 is a common and critical regulator essential for proliferation of embryonic/adult HSCs and transformed leukemic cells.