EVIDENCE FOR DISTINCT REGULATION PROCESSES IN THE ACLACINOMYCIN-MEDIATED AND DOXORUBICIN-MEDIATED DIFFERENTIATION OF HUMAN ERYTHROLEUKEMIC CELLS

Human erythroleukemic K 562 cells were induced to differentiate along the erythroid lineage by anthracycline antitumor drugs, such as aclaci nomycin (ACLA) and doxorubicin (DOX). Subsequent stimulation of heme a nd globin synthesis led to a differential quantitative expression of h emoglobins. Gower 1 (epsilon(2) ,zeta(2)) was the major type for ACLA and X (epsilon(2), gamma(2)) for DOX. Although ACLA and DOX increased both the expression of gamma-globin and porphobilinogen deaminase mRNA s, striking differences were observed in the expression of erythropoie tin receptor mRNAs and in erythroid transcription factors GATA-1 and N F-E2, known to play a key role in erythroid gene regulation. Indeed, A CLA induces an increase either in the binding capacity of GATA-1 and N F-E2 or in the accumulation of erythropoietin receptor, GATA-1 and NF- E2 transcripts. In contrast, their expression with DOX was not signifi cantly modified compared to uninduced cells, except for a slight decre ase in NF-E2 expression on day 3. In conclusion, these data show that: 1. increased expression of erythroid transcription factors and erythr oid genes are associated only with ACLA treatment, and 2. although cyt otoxicity of both ACLA and DOX is certainly dependent on DNA intercala tion, regulation of differentiation processes by these two drugs invol ves distinct mechanisms.