A Review of Cis-Trans Interplay Between DNA Sequences 5′ to the Gγ- and β-Globin Genes Among Hb F-Malta-I Heterozygotes/Homozygotes and β-Thalassemia Homozygotes/Compound Heterozygotes, and the Effects of Hydroxyurea on the Hb F/F-Erythrocyte; the Need for Large Multicenter Trials

The biosynthesis of Hb F in place of the deficient Hb A could be a suitable treatment for β hemoglobinopathies. Among newborn Hb F-Malta-I heterozygotes, it could be shown that the XmnI sequence alone had little, if any effect on γ-globin gene expression, but interplay with the (AT)XTY sites in cis and in trans may occur. In contrast, while the XmnI sequence is clearly correlated with γ-globin levels in anemic adult β-thalassemia (thal) homozygotes, the effect on F-erythrocyte numbers and Hb F/F-erythrocyte appears independent of the (AT)XTY sites. Even at levels of hydroxyurea (HU) as low as 1.65 mg/kg/day (vs. 10 mg/kg/day on the high dose regime) it can be shown that although even a small increase of Hb F could be obtained, the effect was rarely translated into an increase in circulating hemoglobin (Hb). In most cases, the elevated Hb F level was dependent on the XmnI sequence and was due to increased numbers of F-erythrocytes or Hb F/F-erythrocyte or both. It seems that the bone marrow of thalassemia ...