All-trans-retinoic (ATRA) treatment of patients with acute promyelocytic leukemia results in differentiation of the malignant cells and a high complete remission rate. ATRA treatment induced granulocytic differentiation in HL-60 cells as assessed by nitroblue tetrazolium (NBT) reduction, but had no effect on non-specific esterase (NSE) straining, as expected in cells maturing along the monocytic lineage. However, our results demonstrate that ATRA (0.1-10 microM) induces expression of the c-fms (monocyte colony-stimulating factor receptor) gene in HL-60 cells. This effect was detectable after 2 days and expression was maximal at 5 days. Similar results were obtained during treatment with cis-retinoic acid (CRA), hexamethylene bisacetamide (HMBA), or dimethyl sulfoxide (DMSO). The results also demonstrate that ATRA-induced c-fms expression is potentiated by exposure to tumor necrosis factor alpha (TNF alpha) or dibutyryl cyclic adenosine monophosphate (cAMP). The induction of c-fms transcripts by ATRA is associated with induction of M-CSF-binding ability, suggesting cell surface expression of the monocyte growth factor receptor. Our results indicate that retinoic acid can induce features of both monocytic and granulocytic differentiation in HL-60 cells.