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Blood. 2018 Nov 22;132(21):2286-2297. doi: 10.1182/blood-2018-05-852277. Epub 2018 Sep 12.

Transferrin receptor 2 is a potential novel therapeutic target for β-thalassemia: evidence from a murine model.

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Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Vita-Salute San Raffaele University, Milan, Italy.
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany; and.
Molecular Medicine Partnership Unit, Heidelberg, Germany.


β-thalassemias are genetic disorders characterized by anemia, ineffective erythropoiesis, and iron overload. Current treatment of severe cases is based on blood transfusion and iron chelation or allogeneic bone marrow (BM) transplantation. Novel approaches are explored for nontransfusion-dependent patients (thalassemia intermedia) who develop anemia and iron overload. Here, we investigated the erythropoietin (EPO) receptor partner, transferrin receptor 2 (TFR2), as a novel potential therapeutic target. We generated a murine model of thalassemia intermedia specifically lacking BM Tfr2: because their erythroid cells are more susceptible to EPO stimulation, mice show improved erythropoiesis and red blood cell morphology as well as partial correction of anemia and iron overload. The beneficial effects become attenuated over time, possibly due to insufficient iron availability to sustain the enhanced erythropoiesis. Germ line deletion of Tfr2, including haploinsufficiency, had a similar effect in the thalassemic model. Because targeting TFR2 enhances EPO-mediated effects exclusively in cells expressing both receptors, this approach may have advantages over erythropoiesis-stimulating agents in the treatment of other anemias.

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