Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage
Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage
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DOI：
10.1073/pnas.0906556106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Kile, Benjamin T.
中科院分区：
文献类型：
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作者：
Kruse, Elizabeth A.;Loughran, Stephen J.;Kile, Benjamin T.
Fli-1和Erg是Ets家族转录因子中关系密切的成员。这两种基因在人类癌症中都有易位，包括尤文氏肉瘤、白血病，以及超过一半的前列腺癌。尽管来自小鼠和人类的证据表明，巨核形成需要Fli-1，正常成人造血干细胞（HSC）调节需要Erg，但它们的确切生理作用仍有待确定。为了阐明Fli-1和Erg在造血过程中的关系，我们对携带这两个基因突变的小鼠进行了分析。我们的研究结果表明，Fli-1与Erg之间存在着深刻的遗传相互作用。双杂合子表现出比单杂合子更显著的表型：严重的血小板减少，巨核细胞数量明显不足，巨核细胞畸形发生的证据，造血干细胞的丢失伴随着造血祖细胞数量的减少。这些结果说明了Fli-1和Erg在正常HSC和巨核细胞的稳态中是不可或缺的，并提示这些转录因子可能共同调节共同的靶基因。
Fli-1 and Erg are closely related members of the Ets family of transcription factors. Both genes are translocated in human cancers, including Ewing's sarcoma, leukemia, and in the case of Erg, more than half of all prostate cancers. Although evidence from mice and humans suggests that Fli-1 is required for megakaryopoiesis, and that Erg is required for normal adult hematopoietic stem cell (HSC) regulation, their precise physiological roles remain to be defined. To elucidate the relationship between Fli-1 and Erg in hematopoiesis, we conducted an analysis of mice carrying mutations in both genes. Our results demonstrate that there is a profound genetic interaction between Fli-1 and Erg. Double heterozygotes displayed phenotypes more dramatic than single heterozygotes: severe thrombocytopenia, with a significant deficit in megakaryocyte numbers and evidence of megakaryocyte dysmorphogenesis, and loss of HSCs accompanied by a reduction in the number of committed hematopoietic progenitor cells. These results illustrate an indispensable requirement for both Fli-1 and Erg in normal HSC and megakaryocyte homeostasis, and suggest these transcription factors may coregulate common target genes.