Department of Pediatrics, Division of Hematology, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Adv Exp Med Biol. 2024;1459:261-287. doi: 10.1007/978-3-031-62731-6_12.
GATA1 is a highly conserved hematopoietic transcription factor (TF), essential for normal erythropoiesis and megakaryopoiesis, that encodes a full-length, predominant isoform and an amino (N) terminus-truncated isoform GATA1s. It is consistently expressed throughout megakaryocyte development and interacts with its target genes either independently or in association with binding partners such as FOG1 (friend of GATA1). While the N-terminus and zinc finger have classically been demonstrated to be necessary for the normal regulation of platelet-specific genes, murine models, cell-line studies, and human case reports indicate that the carboxy-terminal activation domain and zinc finger also play key roles in precisely controlling megakaryocyte growth, proliferation, and maturation. Murine models have shown that disruptions to GATA1 increase the proliferation of immature megakaryocytes with abnormal architecture and impaired terminal differentiation into platelets. In humans, germline GATA1 mutations result in variable cytopenias, including macrothrombocytopenia with abnormal platelet aggregation and excessive bleeding tendencies, while acquired GATA1s mutations in individuals with trisomy 21 (T21) result in transient abnormal myelopoiesis (TAM) and myeloid leukemia of Down syndrome (ML-DS) arising from a megakaryocyte-erythroid progenitor (MEP). Taken together, GATA1 plays a key role in regulating megakaryocyte differentiation, maturation, and proliferative capacity. As sequencing and proteomic technologies expand, additional GATA1 mutations and regulatory mechanisms contributing to human diseases of megakaryocytes and platelets are likely to be revealed.
GATA1 是一种高度保守的造血转录因子（TF），对正常的红细胞生成和巨核细胞生成至关重要，它编码全长的主要同工型和氨基（N）端截断的同工型 GATA1s。它在巨核细胞发育过程中始终表达，并与靶基因相互作用，无论是独立作用还是与结合伙伴（如 FOG1）一起作用。虽然 N 端和锌指经典上被证明是正常调节血小板特异性基因所必需的，但鼠模型、细胞系研究和人类病例报告表明，羧基末端激活域和锌指也在精确控制巨核细胞生长、增殖和成熟中发挥关键作用。鼠模型表明，GATA1 的破坏会增加不成熟巨核细胞的增殖，这些细胞具有异常的结构和受损的血小板终末分化。在人类中，种系 GATA1 突变导致可变的细胞减少症，包括巨血小板减少症伴有异常血小板聚集和过度出血倾向，而在 21 三体（T21）个体中获得的 GATA1 突变导致短暂性异常髓样增生（TAM）和唐氏综合征的髓样白血病（ML-DS），源自巨核细胞-红细胞祖细胞（MEP）。总之，GATA1 在调节巨核细胞分化、成熟和增殖能力方面发挥着关键作用。随着测序和蛋白质组学技术的扩展，可能会发现更多导致人类巨核细胞和血小板疾病的 GATA1 突变和调节机制。
