The beta-thalassemias are the commonest blood disorder resulted from a number of genetic defects in beta-globin gene expression. Previously, our group and others have shown that hydroxyurea (HU) can augment fetal hemoglobin synthesis in patients with sickle cell anemia, and, to a lesser degree, in patients with beta -thalassemia. However, the mechanism of the action remains unknown. Recently, we analysed the effects of daily lower dosage of HU administration in eight beta- thalassemia patients. Globin mRNA amounts and globin chain biosynthesis pre-and post-HU treatment were investigated by using our newly developed competitive, reversee transcriptase polymerase chain reaction (RT-PCR) and micro-biosynthetic test, respectively. Two patients showed an increase of at least 2-fold in Hb F levels and of 5-fold in gamma-globin mRNA. Curiously, two other patients with beta-thalassemia intermedia who were heterozygous for the IVS-2-654 C->T splicing mutation, with the other beta-allele normal from position -100 to the 3' poly A site, showed an obvious increase primarily in beta-globin biosynthesis, corresponding to an increase in beta-globin mRNA without a significant change in gamma globin synthesis. This was accompanied by an apparent clinical improvement and more effective erythropoiesis with an increase in absolute reticulocyte count and hemoglobin concentration. Thus, in addition to its effects in stimulating gamma-globin synthesis, HU may be useful in the context of treatment of beta-thalassemia through other mechanisms. Current studies in progress are aimed (1) to determine whether particular beta-thalassemia mutations are more susceptible to globin enhancing effects, (2) to define the unknown mutation or silent mutant sequences in the other beta-allele in the two patients who have shown an enhancement of beta-globin gene expression in these-homozygous and heterozygous beta-thalassemia individuals, using competitive RT-PCR method.
