Inhibition of β-globin gene expression by 3′-azido-3′-deoxythymidine in human erythroid progenitor cells

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3′-Azido-3′-deoxythymidine (AZT) treatment in HIV-infected patients is limited by bone marrow suppression including neutropenia and anemia. Previous studies had shown a direct effect of high concentrations of this drug on globin gene expression in K-562 erythroleukemia cells. To better define the mechanism(s) of AZT-induced bone marrow toxicity, the present study evaluates these effects in more relevant human erythroid progenitor liquid cultures, because AZT is 100 times more toxic to human bone marrow cells than K-562 cells. At a clinically relevant concentration of 1 μM, AZT inhibited specifically erythroid cell growth by ∼58% as compared with untreated cells. The percentage of cells synthesizing hemoglobin was decreased also by 47% in AZT-treated cells with β-globin mRNA levels accounting for 0.27 pmol in treated cells as compared with 1.44 under control conditions while β-actin levels remained unchanged. Under the same conditions, AZT inhibited the β-globin chain synthesis by ∼60% as compared with the control. Consistent with the data described above was the finding that a concentration as low as 0.1 μM of AZT decreased by almost 40% the binding level of the erythroid-specific transcription factor GATA-1. These findings demonstrate that AZT, at clinical relevant concentrations, specifically inhibits β-globin gene expression in human erythroid progenitor liquid cell culture.