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Blood. 2017 Mar 16;129(11):1514-1526. doi: 10.1182/blood-2016-09-742387. Epub 2017 Feb 1.

Decreasing TfR1 expression reverses anemia and hepcidin suppression in β-thalassemic mice.

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Hunan Key Laboratory of Carcinogenesis and Cancer Invasion, Cancer Research Institute, Central South University, Ministry of Education, Changsha, China.
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY.
Erythropoiesis Laboratory, New York Blood Center, New York, NY.
State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, China.
University of Piemonte Orientale, Amedeo Avogadro, Novara, Italy.
Jewish General Hospital, Lady Davis Institute, McGill University, Montreal, QC, Canada.
Laboratory of Membrane Biology, New York Blood Center, New York, NY.
Flow Cytometry Core Laboratory, Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY.
Saint Louis University, Saint Louis, MO; and.
Children's Hospital of Philadelphia, Philadelphia, PA.


Iron availability for erythropoiesis and its dysregulation in β-thalassemia are incompletely understood. We previously demonstrated that exogenous apotransferrin leads to more effective erythropoiesis, decreasing erythroferrone (ERFE) and derepressing hepcidin in β-thalassemic mice. Transferrin-bound iron binding to transferrin receptor 1 (TfR1) is essential for cellular iron delivery during erythropoiesis. We hypothesize that apotransferrin's effect is mediated via decreased TfR1 expression and evaluate TfR1 expression in β-thalassemic mice in vivo and in vitro with and without added apotransferrin. Our findings demonstrate that β-thalassemic erythroid precursors overexpress TfR1, an effect that can be reversed by the administration of exogenous apotransferrin. In vitro experiments demonstrate that apotransferrin inhibits TfR1 expression independent of erythropoietin- and iron-related signaling, decreases TfR1 partitioning to reticulocytes during enucleation, and enhances enucleation of defective β-thalassemic erythroid precursors. These findings strongly suggest that overexpressed TfR1 may play a regulatory role contributing to iron overload and anemia in β-thalassemic mice. To evaluate further, we crossed TfR1+/- mice, themselves exhibiting iron-restricted erythropoiesis with increased hepcidin, with β-thalassemic mice. Resultant double-heterozygote mice demonstrate long-term improvement in ineffective erythropoiesis, hepcidin derepression, and increased erythroid enucleation in relation to β-thalassemic mice. Our data demonstrate for the first time that TfR1+/- haploinsufficiency reverses iron overload specifically in β-thalassemic erythroid precursors. Taken together, decreasing TfR1 expression during β-thalassemic erythropoiesis, either directly via induced haploinsufficiency or via exogenous apotransferrin, decreases ineffective erythropoiesis and provides an endogenous mechanism to upregulate hepcidin, leading to sustained iron-restricted erythropoiesis and preventing systemic iron overload in β-thalassemic mice.

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