Ineffective erythropoiesis (IE) is defined as the abnormal differentiation and excessive destruction of erythroblasts in the marrow, accompanied by an expanded progenitor compartment and relative reduction in the production of reticulocytes. It is a defining feature of many types of anemia, including beta-thalassemia. GATA1 is an essential transcription factor for erythroid differentiation, known to be implicated in hematological conditions presenting with IE, including beta-thalassemia and congenital dyserythropoietic anemia. However, little is known about the role of GATA1 in the erythropoietic defects recently described in sickle cell anemia (SCA). In the present study, we performed a detailed characterization of the role of GATA1 and ineffective erythropoiesis in SCA using both invitro and in-vivo assay systems. We demonstrate a significant decrease in GATA1 protein levels during SCA erythropoiesis and a concomitant increase in oxidative stress. Furthermore, we found that an increase in the activity of the inflammatory caspase, caspase 1, was driving the decrease in GATA1 levels during SCA erythropoiesis and that, upon inhibition of caspase 1 activity, SCA erythropoiesis was rescued and GATA1 levels partially restored. Our study further elucidates the defect in erythropoiesis in SCA, and may therefore help in the development of novel approaches to normalise the bone marrow niche prior to stem cell transplantation, or facilitate the production of healthy stem cells for gene therapy.

中文翻译：

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GATA1 水平降低与镰状细胞性贫血中的无效红细胞生成有关。


无效红细胞生成 （IE） 定义为骨髓中成红细胞的异常分化和过度破坏，伴有祖细胞室扩大和网织红细胞产生的相对减少。它是许多类型贫血（包括 β-地中海贫血）的定义特征。GATA1 是红细胞分化的重要转录因子，已知与表现为 IE 的血液病有关，包括 β-地中海贫血和先天性红细胞生成障碍性贫血。然而，关于 GATA1 在最近描述的镰状细胞性贫血 （SCA） 红细胞生成缺陷中的作用知之甚少。在本研究中，我们使用体外和体内检测系统对 GATA1 和无效红细胞生成在 SCA 中的作用进行了详细表征。我们证明 SCA 红细胞生成期间 GATA1 蛋白水平显着降低，伴随着氧化应激的增加。此外，我们发现炎性半胱天冬酶 caspase 1 活性的增加导致 SCA 红细胞生成期间 GATA1 水平的降低，并且在抑制 caspase 1 活性后，SCA 红细胞生成得到挽救，GATA1 水平部分恢复。我们的研究进一步阐明了 SCA 红细胞生成缺陷，因此可能有助于开发新的方法，使干细胞移植前骨髓生态位正常化，或促进产生用于基因治疗的健康干细胞。