Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Institute of Molecular Biosciences, Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.
Acta Haematol. 2021;144(6):660-671. doi: 10.1159/000518310. Epub 2021 Sep 14.
β-Thalassemia/hemoglobin E represents one-half of all the clinically severe β-thalassemias worldwide. Despite similar genetic backgrounds, patients show clinical heterogeneity ranging from nearly asymptomatic to transfusion-dependent thalassemia. The underlying disease modifying factors remain largely obscure.
To elucidate the correlation between ineffective erythropoiesis and β0-thalassemia/hemoglobin E (HbE) disease severity, in vitro culture of erythroid cells derived from patients with different clinical symptoms was established. Cell proliferation, viability, and differentiation were investigated. To identify potential molecular mechanisms leading to the arrested erythroid maturation, the expression levels of erythropoiesis modifying factors were measured.
The β0-thalassemia/HbE cells exhibited enhanced proliferation, limited differentiation, and impaired erythroid terminal maturation but did not show accelerated erythroblast differentiation and increased cell death. Erythroblasts derived from mild patients showed the highest proliferation rate with a faster cell division time, while erythroblasts derived from severe patients displayed extremely delayed erythroid maturation. Downregulation of growth differentiation factor 11 and FOXO3a was observed in mild β0-thalassemia/HbE erythroblasts, while upregulation of heat shock protein 70 and activin receptor 2A was revealed in severe erythroblasts.
DISCUSSION/CONCLUSION: The degree of erythroid expansion and maturation arrest contributes to the severity of β0-thalassemia/HbE patients, accounting for the disease heterogeneity. The findings suggest a restoration of erythroid maturation as a promising targeted therapy for severe patients.
β-地中海贫血/血红蛋白 E 占全球所有临床重度β-地中海贫血的一半。尽管具有相似的遗传背景，但患者表现出从几乎无症状到依赖输血的地中海贫血等临床异质性。潜在的疾病修饰因子仍很大程度上不清楚。
为了阐明无效红细胞生成与β0-地中海贫血/血红蛋白 E（HbE）疾病严重程度之间的相关性，建立了来自不同临床症状患者的红系细胞的体外培养。研究了细胞增殖、活力和分化。为了确定导致红细胞成熟停滞的潜在分子机制，测量了红细胞生成修饰因子的表达水平。
β0-地中海贫血/HbE 细胞表现出增强的增殖、有限的分化和受损的红细胞终末成熟，但没有表现出加速的成红细胞分化和增加的细胞死亡。轻度患者来源的红细胞表现出最高的增殖率和更快的细胞分裂时间，而重度患者来源的红细胞显示出极其延迟的红细胞成熟。在轻度β0-地中海贫血/HbE 红细胞中观察到生长分化因子 11 和 FOXO3a 的下调，而在重度红细胞中观察到热休克蛋白 70 和激活素受体 2A 的上调。
讨论/结论：红细胞扩张和成熟停滞的程度导致β0-地中海贫血/HbE 患者的严重程度，导致疾病异质性。研究结果表明，恢复红细胞成熟可能是治疗重度患者的一种有前途的靶向治疗方法。
