ANTHRACYCLINES AS TUMOR-CELL DIFFERENTIATING AGENTS - EFFECTS ON THE REGULATION OF ERYTHROID GENE-EXPRESSION

Tumor cells, and particularly leukemic cells, can be considered as mat uration-arrested cells which have escaped some normal control and cont inue to proliferate. This maturation arrest can be reversed by differe ntiation agents such as antitumor drugs currently used in conventional cytotoxic chemotherapy. In this respect, anthracyclines have been sho wn to trigger the differentiation of leukemic and solid tumor cells, b ut the molecular mechanisms by which such drugs lead to the differenti ating phenotype are still poorly understood, Using human leukemic mult ipotent K562 cells, we have demonstrated that subtoxic concentrations of aclacinomycin (ACLA) and doxorubicin (DOX) preferentially stimulate the hemoglobinic pathway (globins and heme synthesis) and the express ion of mRNAs of globins and of porphobilinogen deaminase (PRGD). Howev er, our results indicate that both drugs exert this differentiating ef fect along distinct regulatory pathways, Indeed, only ACLA and nor DOX induces the expression of erythropoietin receptor (EpoR) mRNAs and of membrane EpoR, as well as an overexpression of the erythroid transcri ption factors GATA-1 and NF-E2 known to play a central role in erythro id gene regulation, Similarly, using transfection assays, ACLA but not DOX activates the regulatory regions (promoters and enchancers) of GA TA-1, EpoR, PBGD, epsilon- and gamma-globin genes. Finally, results of run-on assays indicate that ACLA induces an enhancement of the transc ription rate of these erythroid genes whereas DOX preferentially incre ases stability of GATA-1, NF-E2 and PBGD mRNAs. In conclusion, ACLA ma inly acts at the transcriptional level sia specific activation of eryt hroid regulatory regions whereas DOX rather acts at the posttranscript ional level by increasing the half-lives of erythroid mRNAs.