Inhibition of beta-globin gene expression by 3 '-azido-3 '-deoxythymidine in human erythroid progenitor cells

3'-Azido-3'-deoxythymidine (AZT) treatment in HIV-infected patients is limi ted by bone marrow suppression including neutropenia and anemia. Previous s tudies had shown a direct effect of high concentrations of this drug on glo bin gene expression in K-562 erythroleukemia cells. To better define the me chanism(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 rimes more toxic to human bone marrow cells than K-562 cells. At a clinically relevant concentration of I mu M, AZT inhibited spec ifically erythroid cell growth by similar to 58% as compared with untreated cells. The percentage of cells synthesizing hemoglobin was decreased also by 47% in AZT-treated cells with beta-globin mRNA levels accounting for 0.2 7 pmol in treated cells as compared with 1.44 under control conditions whil e beta-actin levels remained unchanged. Under the same conditions, AZT inhi bited the beta-globin chain synthesis by similar to 60% as compared with th e control. Consistent with the data described above was the finding that a concentration as low as 0.1 mu M of AZT decreased by almost 40% the binding level of the erythroid-specific transcription factor GATA-1. These finding s demonstrate that AZT, at clinical relevant concentrations, specifically i nhibits beta-globin gene expression in human erythroid progenitor liquid ce ll culture. (C) 1999 Elsevier Science B.V. All rights reserved.