beta-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for beta-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor beta pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbb(th3/+) thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbb(th3/+) mice with or without hematopoietic Tfr2 (Tfr2(BMKO)/Hbb(th3/+)) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbb(th3/+) and Tfr2(BMKO)/Hbb(th3/+) animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps.

Bone marrow Tfr2 deletion improves the therapeutic efficacy of the activin-receptor ligand trap RAP-536 in β-thalassemic mice / Tanzi, Emanuele; Di Modica, Simona Maria; Bordini, Jessica; Olivari, Violante; Pagani, Alessia; Furiosi, Valeria; Silvestri, Laura; Campanella, Alessandro; Nai, Antonella. - In: AMERICAN JOURNAL OF HEMATOLOGY. - ISSN 1096-8652. - (2024). [10.1002/ajh.27336]

Bone marrow Tfr2 deletion improves the therapeutic efficacy of the activin-receptor ligand trap RAP-536 in β-thalassemic mice

Tanzi, Emanuele
Primo
;
Bordini, Jessica;Olivari, Violante;Pagani, Alessia;Campanella, Alessandro
Penultimo
;
2024-01-01

Abstract

beta-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for beta-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor beta pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbb(th3/+) thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbb(th3/+) mice with or without hematopoietic Tfr2 (Tfr2(BMKO)/Hbb(th3/+)) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbb(th3/+) and Tfr2(BMKO)/Hbb(th3/+) animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/161036
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