Effects of Novel Retinoic Acid Compound, 9-cis-Retinoic Acid, on Proliferation, Differentiation, and Expression of Retinoic Acid Receptor-a

Retinoic acid modulates proliferation and differentiation of a wide variety of normal and leukemic cells through two distinct families of transcriptional factors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). A stereoisomer of retinoic acid, 9-cis-retinoic acid, is a highaffinity ligand for RXR and binds efficiently to RAR. In contrast, all-trans-retinoic acid interacts 40-fold less efficiently with RXR as compared with RAR. To clarify the biologic role of retinoic acid compounds (all-trans,9-cis-, and 13-cis-retinoic acid) in hematopoietic cells, we studied their effects on clonal growth, differentiation, and expression of RAR-a and RXR-a genes in HL-60 cells. At very low concentrations (1 0-l5 to 1 O-’* mmol/L), each retinoid enhanced clonal growth of HL-60 cells. These concentrations of the retinoids had no capacity to induce differentiation of leukemic cells as measured by ability either to reduce nitroblue tetrazolium and to express CDI l b antigens, suggesting that retinoids at very low concentrations may stimulate proliferation of leukemic cells rather than induce their