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 Blood, 7 May 2009, Vol. 113, No. 19, pp. 4763-4770.
Prepublished online as a Blood First Edition Paper on March 3, 2009; DOI 10.1182/blood-2008-12-197012.

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RED CELLS, IRON, AND ERYTHROPOIESIS

Preclinical transfusion-dependent humanized mouse model of β thalassemia major

Yongliang Huo1, Sean C. McConnell1, and Thomas M. Ryan1

1 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham

A preclinical humanized mouse model of β thalassemia major or Cooley anemia (CA) was generated by targeted gene replacement of the mouse adult globin genes in embryonic stem cells. The mouse adult {alpha} and β globin genes were replaced with adult human {alpha} globin genes ({alpha}2{alpha}1) and a human fetal to adult hemoglobin (Hb)–switching cassette ({gamma}HPFH{delta}β0), respectively. Similar to human infants with CA, fully humanized mice survived postnatally by synthesizing predominantly human fetal Hb, HbF ({alpha}2{gamma}2), with a small amount of human minor adult Hb, HbA2 ({alpha}2{delta}2). Completion of the human fetal to adult Hb switch after birth resulted in severe anemia marked by erythroid hyperplasia, ineffective erythropoiesis, hemolysis, and death. Similar to human patients, CA mice were rescued from lethal anemia by regular blood transfusion. Transfusion corrected the anemia and effectively suppressed the ineffective erythropoiesis, but led to iron overload. This preclinical humanized animal model of CA will be useful for the development of new transfusion and iron chelation regimens, the study of iron homeostasis in disease, and testing of cellular and genetic therapies for the correction of thalassemia.


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