Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
J Clin Invest. 2012 Oct;122(10):3692-704. doi: 10.1172/JCI61623. Epub 2012 Sep 10.
Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2 cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.
GATA2 部分功能缺失导致人类免疫缺陷综合征，其特征为分枝杆菌感染、骨髓增生异常、淋巴水肿或再生障碍性贫血，进而发展为骨髓性白血病。GATA2 编码造血的主要调节因子，也与内皮生物学有关。尽管致病突变通常发生在 GATA-2 DNA 结合域，但我们发现了一名分枝杆菌感染和骨髓增生异常的患者，其 GATA2 顺式元件（由 E 盒和 GATA 基序组成）存在未表征的杂合缺失。靶向敲除产生纯合突变鼠的等效鼠元素揭示了胚胎致死时间晚于全局 Gata2 敲除、造血干细胞/祖细胞耗竭和血管完整性受损的时间。杂合突变鼠是有活力的，但胚胎表现出明显的造血干细胞/祖细胞活性缺陷，而原始造血干细胞/祖细胞活性不受影响，并且 Gata2 及其靶基因的表达减少。机制分析显示内皮细胞转录组中断和血管完整性丧失。因此，在人类免疫缺陷中被破坏的复合元件对于在胎肝中建立鼠造血干细胞/祖细胞区室以及对于基本的血管过程是必需的。
