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

Abstract

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 homozygotes may be more sensitive to myelosuppression by HU possibly due to medullary inflammation. While the data are consistent with loop models of globin switching mechanisms, there is urgent need for large, hypothesis driven, multicenter trials of molecules that could maintain or re-induce high Hb F levels in β-thal and subject to genetic and epigenetic constraints including inflammation.