We have previously demonstrated that continuous exposure of human HL-60 human promyelocytes to 1-beta-D-arabinofuranosylcytosine (ara-C) results in the induction of terminal differentiation to monocyte-like cells. The present study extends these findings by demonstrating that ara-C induces hemoglobin synthesis in human K562 erythroleukemia cells. This effect occurs maximally at an ara-C concentration (5 X 10(-7) M) that results in K562 cytostasis. In contrast to the reversible effects of hemin and hydroxyurea on globin synthesis in this cell line, we have found that the induction of K562 hemoglobin synthesis by ara-C is irreversible. An induction of K562 hemoglobin synthesis also occurs with aphidicolin, another inhibitor of S-phase DNA synthesis, but not with vinblastine, an inhibitor of mitosis. Finally, ara-C induction of a differentiated K562 phenotype is accompanied by the loss of self-renewal capacity, a finding consistent with terminal differentiation.