Effects of simultaneous and sequential exposure to granulocytic and monocytic inducers on the choice of differentiation pathway in HL-60 promyelocytic leukemia cells.

HL-60 promyelocytic leukemic cells were induced to differentiate by the combination of two alternative inducers: phorbol-12-myristate 13-acetate (PMA) and either dimethyl sulfoxide (DMSO) or retinoic acid (RA). Simultaneous exposure to optimal concentrations of PMA and either DMSO or RA potentiated PMA-induced differentiation into monocyte-macrophages. Granulocytic inducers combined with lower concentration of PMA competed with the latter for the differentiation pathway, producing monocyte-macrophages, granulocytes, paramyeloid and giant multinucleated cells. Lineage specificity of cells treated sequentially with two discrete exposures to alternative inducers depended on the order of exposure. The first exposure initiated differentiation into the pathway specific for the inducer used. The second exposure determined lineage specificity and stimulated terminal differentiation. Thus, treatment with RA for 24-72 h followed by PMA resulted in monocyte-macrophage differentiation; reversed order of exposure resulted in granulocytic differentiation. The switch in the differentiation pathway occurred at the relatively advanced stages of differentiation.