Gene expression analysis of the hydroxyurea response in primary erythroid progenitors derived from β-thalassemia patients

摘要: The β-thalassemia is caused by mutations in the β-globin gene locus that cause loss or reduction of β-globin gene expression. Hydroxyurea (HU) increases expression of fetal β-globin in postnatal life, and is therefore an appealing therapeutic approach to the β-thalassemias. Patients treated with HU fall into three categories:(i)‘Good responders’ increase hemoglobin to therapeutic levels (ii)‘Moderate responders’ increase hemoglobin levels but still need transfusions at longer intervals, and (iii)‘non-responders’, who remain transfusion-dependent. The mechanisms underlying these differential responses remain unclear. We generated RNA expression profiles of erythroblasts grown in the presence or absence of HU that were expanded from blood of 16 β-thalassemia patients that responded either very poor (non-responders) or very good (responders) to HU treatment. RNA expression profiles showed that the cells derived from responders, follow the pattern of genes involved in terminal erythroid differentiation stronger than non-responders. Many genes were upregulated in response to HU in erythroblasts from non-responders, including γ-globin. However, the γ-globin starting level was low in these cases and HU treatment induced significant cell death. In contrast, HU treatment of erythroblasts from responders had little impact on their gene expression profiles. Their γ-globin was upregulated, but the baseline level of γ-globin was already high. Interestingly, part of the gene program that was upregulated by HU in non-responder erythroblasts was already highly expressed in the erythroblasts of responders before HU treatment. We conclude from …