Fetal expression of a human A gamma globin transgene rescues globin chain imbalance but not hemolysis in EKLF null mouse embryos

Mice lacking the erythroid Kruppel-like factor (EKLF) die in utero at embry onic day 15 (E15) from severe anemia. EKLF-/- embryos display a marked defi cit in beta-globin gene expression. To test whether beta-globin deficiency was solely responsible for the anemia and intrauterine death, we corrected the globin chain imbalance in EKLF-/- embryos by breeding with a strain of mice that express high levels of human gamma-globin, Despite efficient prod uction of hybrid m alpha(2)-h gamma(2) hemoglobin in the fetal livers of EK LF-/- animals, hemolysis was not corrected and survival was not prolonged. We concluded that deficiency of nonglobin EKLF target genes is a major cont ributor to the definitive red blood cell abnormalities and prenatal death i n EKLF-/- embryos. These results suggest that strategies designed to antago nize EKLF function in adults with hemoglobinopathy, in an attempt to reacti vate gamma-globin gene expression, may adversely affect other essential asp ects of red blood cell physiology. (C) 2000 by The American Society of Hema tology.