Transferrin receptor 2 (Tfr2) genetic deletion makes transfusion-independent a murine model of transfusion-dependent ß-thalassemia.
Am J Hematol
; 97(10): 1324-1336, 2022 10.
Article
en En
| MEDLINE
| ID: mdl-36071579
ABSTRACT
ß-thalassemia is a genetic disorder caused by mutations in the ß-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 iron-restricting 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 Hbbth1/th2 murine model of TDT. This effect is associated with a decrease in the expression of α-globin, which partially corrects the unbalance with ß-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 Hbbth1/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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Receptores de Transferrina
/
Talasemia beta
/
Sobrecarga de Hierro
Límite:
Animals
Idioma:
En
Revista:
Am J Hematol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Italia