Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression
Oncogenic transcription factor Evi1 regulates hematopoietic stem cell proliferation through GATA-2 expression
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DOI：
10.1038/sj.emboj.7600679
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发表时间：
2005-06-01
期刊：
影响因子：
11.4
通讯作者：
Morishita, K
中科院分区：
文献类型：
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作者：
Yuasa, H;Oike, Y;Morishita, K
亲嗜性病毒整合位点-1（Evi 1）是小鼠和人髓性白血病中的致癌转录因子。我们在此表明，Evi 1主要在胚胎和成人骨髓的造血干细胞（HSC）中表达，这表明Evi 1在HSC中的生理作用。因此，我们调查的作用和真实的靶基因Evi 1造血使用Evi 1（-/-）小鼠，在胚胎第10.5天死亡。Evi1（-/-）胚胎中的HSC在体内数量明显减少，自我更新增殖和再增殖能力缺陷。值得注意的是，加塔-2 mRNA的表达率，这是必不可少的永久性HSC的增殖，是深刻的Evi 1（-/-）胚胎的HSC减少。恢复Evi 1（-/-）HSC中Evi 1或加塔-2的表达可通过上调加塔-2的表达来防止HSC体外维持和增殖的失败。对加塔-2启动子区的分析显示Evi 1作为增强子直接结合加塔-2启动子。我们的研究结果表明，加塔-2可能是Evi 1的关键目标之一，转录因子调节HSC池分级。
The ecotropic viral integration site-1 (Evi1) is an oncogenic transcription factor in murine and human myeloid leukemia. We herein show that Evi1 is predominantly expressed in hematopoietic stem cells (HSCs) in embryos and adult bone marrows, suggesting a physiological role of Evi1 in HSCs. We therefore investigate the role and authentic target genes of Evi1 in hematopoiesis using Evi1(-/-) mice, which die at embryonic day 10.5. HSCs in Evi1(-/-) embryos are markedly decreased in numbers in vivo with defective self-renewing proliferation and repopulating capacity. Notably, expression rate of GATA-2 mRNA, which is essential for proliferation of definitive HSCs, is profoundly reduced in HSCs of Evi1(-/-) embryos. Restoration of the Evi1 or GATA-2 expression in Evi1(-/-) HSCs could prevent the failure of in vitro maintenance and proliferation of HSC through upregulation of GATA-2 expression. An analysis of the GATA-2 promoter region revealed that Evi1 directly binds to GATA-2 promoter as an enhancer. Our results reveal that GATA-2 is presumably one of critical targets for Evi1 and that transcription factors regulate the HSC pool hierarchically.