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

Autor: Di Modica SM; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy., Tanzi E; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy., Olivari V; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy., Lidonnici MR; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Ospedale San Raffaele, Milan, Italy., Pettinato M; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy., Pagani A; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy., Tiboni F; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Ospedale San Raffaele, Milan, Italy., Furiosi V; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy., Silvestri L; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy., Ferrari G; Vita Salute San Raffaele University, Milan, Italy.; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Ospedale San Raffaele, Milan, Italy., Rivella S; Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Nai A; Regulation of Iron Metabolism Unit, Division of Genetics and Cell Biology, Ospedale San Raffaele, Milan, Italy.; Vita Salute San Raffaele University, Milan, Italy.
Jazyk: angličtina
Zdroj: American journal of hematology [Am J Hematol] 2022 Oct; Vol. 97 (10), pp. 1324-1336. Date of Electronic Publication: 2022 Aug 10.
DOI: 10.1002/ajh.26673
Abstrakt: 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 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 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.
(© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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