Metabolic reprogramming during ineffective erythropoiesis in β-thalassemia/HbE disease

Ineffective erythropoiesis, the main cause of anemia in β-thalassemia disease, is characterized by dramatic expansion of erythroblasts and increased erythroblast cell death. The absence or reduction of β-globin chains causes an accumulation of excess α-globin chains and generates cytotoxic reactive oxidant species, resulting in erythroblast cell death. Metabolism provides energy, building blocks for macromolecule synthesis, and cofactors for antioxidative defense systems. We hypothesized that β-thalassemia erythroblasts might alter their metabolism to cope with increased proliferation and cellular stress. Herein, transcriptomic analysis of basophilic and polychromatic erythroblasts isolated from bone marrow obtained from β-thalassemia/HbE patients showed the global up-regulation of metabolic genes in glycolysis, TCA cycle, pentose phosphate pathway, ATP, and fatty acid synthesis pathway. The expression of metabolic genes during terminal erythropoiesis was further determined by PCR array and RT-qPCR in erythroblast culture obtained from β-thalassemia/HbE patients with mild and severe symptoms. The increased expression of enolase1, isocitrate dehydrogenase 1, and bisphosphoglycerate mutase was observed in mild cases compared to severe patients, suggesting that mild patients might modulate metabolic flux for cellular stress defense mechanisms, reducing disease severity. Moreover, the role of BPGM in regulating erythroid differentiation was demonstrated in K562 cells. Inhibition of BPGM promotes cell differentiation in K562 cells. Understanding metabolic reprogramming in thalassemia erythropoiesis opens new therapeutic approaches for β-thalassemia/HbE treatment. Further research is needed to explore how metabolism affects ineffective erythropoiesis and supports thalassemic erythroblasts' high proliferation and oxidative stress defense.