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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, 2007February 13, 2007; DOI 10.1182/blood-2006-09-048868.
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Submitted September 26, 2006
Accepted February 4, 2007
Ineffective erythropoiesis in  -thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin
Sara Gardenghi, Maria F Marongiu, Pedro Ramos, Ella Guy, Laura Breda, Amy Chadburn, YiFang Liu, Ninette Amariglio, Gideon Rechavi, Eliezer A Rachmilewitz, William Breuer, Z. Ioav Cabantchik, Diedra M Wrighting, Nancy C Andrews, Maria de Sousa, Patricia J Giardina, Robert W Grady, and Stefano Rivella*
Dept of Pediatric Hematology-Oncology, Children's Blood Foundation Laboratories, Weill Medical College of Cornell University, New York, NY, United States
Iron Genes & Immune System (IRIS Lab), IBMC-Instituto de Biologia Molecular e Celular, Oporto University, Oporto, Portugal
Dept of Pathology and Laboratory of Medicine, Weill Medical College of Cornell University, New York, NY, United States
Dept of Pediatric Hematology-Oncology, and Institute of Hematology, Chaim Sheba Medical Center, Tel Aviv University, Tel-Aviv, Israel
Dept of Hematology, Hadassah Medical Center and School of Medicine, The Hebrew University, Jerusalem, Israel
Dept of Biological Chemistry, Institute of Life Science, The Hebrew University, Jerusalem, Israel
Children's Hospital and Harvard Medical School, Boston, MA, United States
* Corresponding author; email: str2010{at}med.cornell.edu.
Progressive iron overload is the most salient and ultimately fatal complication of  -thalassemia. However, little is known about the relationship between ineffective erythropoiesis (IE), the role of iron-regulatory genes and tissue iron distribution in -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 -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 -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 -thalassemia.
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