Reducing erythroblast apoptosis in β-thalassemia via unfolded protein response (UPR) signaling

Abstract

Apoptosis plays an important role in ineffective erythropoiesis in β-thalassemia. This early destruction causes severe anemia and contributes significantly to patient mortality. There are several treatment options for this disorder based on the use of drugs that inhibit the destruction of immature erythrocytes in the bone marrow. However, the clinical effectiveness of these drugs has yet to be proven. Therefore, new targets for more effective treatments are needed. The unfolded protein response (UPR) is a biological process that occurs in response to endoplasmic reticulum (ER) stress. To cope with ER stress, unfolded or misfolded proteins activate the UPR pathway, thereby activating a series of cell death pathways. Here, we propose that prolonged ER stress causes apoptosis via UPR signaling during erythroid development in β-thalassemia. Our proposed hypothesis is supported by 1) the involvement of UPR signaling in apoptotic cell death, 2) changes in UPR-related proteins in β-thalassemia, and 3) the availability of UPR signaling inhibitors. In vitro and in vivo studies should be conducted to identify the proteins that participate in the UPR pathway and identify molecular targets for therapy. The β-thalassemia mouse model could be used to evaluate the efficacy of UPR mimic drugs prior to clinical trials. If verified, gaining control over cell fate determination during UPR signaling in β-thalassemia may minimize erythroblast destruction.