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Blood, 1 June 2007, Vol. 109, No. 11, pp. 5027-5035.
Prepublished online as a Blood First Edition Paper on February 15, 2007; DOI 10.1182/blood-2006-09-048868.
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RED CELLS
Ineffective erythropoiesis in β-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin
Sara Gardenghi1,
Maria F. Marongiu1,
Pedro Ramos1,2,
Ella Guy1,
Laura Breda1,
Amy Chadburn3,
YiFang Liu3,
Ninette Amariglio4,
Gideon Rechavi4,
Eliezer A. Rachmilewitz5,
William Breuer6,
Z. Ioav Cabantchik6,
Diedra M. Wrighting7,
Nancy C. Andrews7,
Maria de Sousa1,2,
Patricia J. Giardina1,
Robert W. Grady1, and
Stefano Rivella1
1 Department of Pediatric Hematology-Oncology, Children's Blood Foundation Laboratories, Weill Medical College of Cornell University, New York, NY;
2 Iron Genes and Immune System (IRIS Lab), Instituto de Biologia Molecular e Celular (IBMC), Oporto University, Oporto, Portugal;
3 Department of Pathology and Laboratory of Medicine, Weill Medical College of Cornell University, New York, NY;
4 Department of Pediatric Hematology-Oncology and Institute of Hematology, Chaim Sheba Medical Center, Tel-Hashomer, Tel-Aviv University, Israel;
5 Department of Hematology, Hadassah Medical Centre and School of Medicine, Hebrew University, Ein-Kerem, Jerusalem, Israel;
6 Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel;
7 Children's Hospital and Harvard Medical School, Boston, MA
Progressive iron overload is the most salient and ultimately fatal complication of β-thalassemia. However, little is known about the relationship among ineffective erythropoiesis (IE), the role of iron-regulatory genes, and tissue iron distribution in β-thalassemia. We analyzed tissue iron content and iron-regulatory gene expression in the liver, duodenum, spleen, bone marrow, kidney, and heart of mice up to 1 year old that exhibit levels of iron overload and anemia consistent with both β-thalassemia intermedia (th3/+) and major (th3/th3). Here we show, for the first time, that tissue and cellular iron distribution are abnormal and different in th3/+ and th3/th3 mice, and that transfusion therapy can rescue mice affected by β-thalassemia major and modify both the absorption and distribution of iron. Our study reveals that the degree of IE dictates tissue iron distribution and that IE and iron content regulate hepcidin (Hamp1) and other iron-regulatory genes such as Hfe and Cebpa. In young th3/+ and th3/th3 mice, low Hamp1 levels are responsible for increased iron absorption. However, in 1-year-old th3/+ animals, Hamp1 levels rise and it is rather the increase of ferroportin (Fpn1) that sustains iron accumulation, thus revealing a fundamental role of this iron transporter in the iron overload of β-thalassemia.
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