Transferrin receptor 2 (Tfr2) genetic deletion makes transfusion‐independent a murine model of transfusion‐dependent β‐thalassemia

Abstract

β-thalassemia is a genetic disorder caused by mutations in the β-globin gene, and characterized by anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe transfusion-dependent form of the disease (TDT) require lifelong blood transfusions and iron chelation therapy, a symptomatic treatment associated with several complications.Other therapeutic opportunities are available, but none is fully effective and/or applicable to all patients, calling for the identification of novel strategies. Transferrin receptor 2 (TFR2) balances red blood cells production according to iron availability, being an activator of the iron-regulatory hormone hepcidin in the liver and a modulator of erythropoietin signaling in erythroid cells. Selective Tfr2 deletion in the BM improves anemia and iron-overload in non-TDT mice, both as a monotherapy and, even more strikingly, in combination with ironrestricting approaches. However, whether Tfr2 targeting might represent a therapeutic option for TDT has never been investigated so far. Here, we prove that BM Tfr2 deletion improves anemia, erythrocytes morphology and ineffective erythropoiesis in the Hbb th1/th2 murine model of TDT. This effect is associated with a decrease in the expression of α-globin, which partially corrects the unbalance with β-globin chains and limits the precipitation of misfolded hemoglobin, and with a decrease in the activation of unfolded protein response. Remarkably, BM Tfr2 deletion is also sufficient to avoid long-term blood transfusions required for survival of Hbb th1/th2 animals, preventing mortality due to chronic anemia and reducing transfusion-associated complications, such as progressive iron-loading. Altogether, TFR2 targeting might represent a promising therapeutic option also for TDT.

Targeting the Second Transferrin Receptor as Emerging Therapeutic Option for β-Thalassemia Major

“…Recently, Di Modica and co‐authors showed how the second transferrin receptor (TfR2) can be exploited for therapeutic purposes in TDT 5 . TfR2 is a transmembrane glycoprotein homologous to the classical transferrin receptor 1 (TfR1).…”

“…TfR2 is a transmembrane glycoprotein homologous to the classical transferrin receptor 1 (TfR1). While TfR1 is ubiquitously expressed and acts as main mechanism for cellular iron uptake through Tf‐bound iron interaction, TfR2 is highly expressed in hepatocytes and rather involved in the regulation of hepcidin expression to modulate systemic iron levels 5 . Importantly, TfR2 was recently described as a sensor of circulating iron in erythroid cells, where it binds the erythropoietin (EPO) receptor (EPOR) and inhibits the activation of the EPO‐EPOR signaling.…”

“…This model recapitulates the phenotype of TDT β-thalassemia major, developing severe anemia and requiring red blood cell transfusions for survival. 5 Transplantation of fetal liver cells of thalassemic embryos carrying Tfr2 deletion, resulting in the abrogation of erythroid TfR2 function, significantly ameliorated anemia and improved erythroid differentiation and RBCs morphology. Bone marrow Tfr2-deleted mice had increased RBC count, hemoglobin levels, and hematocrit and decreased reticulocytes.…”

“…Recently, Di Modica and co-authors showed how the second transferrin receptor (TfR2) can be exploited for therapeutic purposes in TDT. 5 TfR2 is a transmembrane glycoprotein homologous to the classical transferrin receptor 1 (TfR1). While TfR1 is ubiquitously expressed and acts as main mechanism for cellular iron uptake through Tf-bound iron interaction, TfR2 is highly expressed in hepatocytes and rather involved in the regulation of hepcidin expression to modulate systemic iron levels.…”

“…While TfR1 is ubiquitously expressed and acts as main mechanism for cellular iron uptake through Tf-bound iron interaction, TfR2 is highly expressed in hepatocytes and rather involved in the regulation of hepcidin expression to modulate systemic iron levels. 5 Importantly, TfR2 was recently described as a sensor of circulating iron in erythroid cells, where it binds the erythropoietin (EPO) receptor (EPOR) and inhibits the activation of the EPO-EPOR signaling. Under condition of elevated Tf saturation, TfR2 is stabilized on the plasma membrane of both hepatocytes, increasing hepcidin to inhibit intestinal iron absorption, and erythroblasts, preventing excessive erythropoietic expansion.…”