RETINOID ACID SUPPORTS GRANULOCYTIC BUT NOT ERYTHROID-DIFFERENTIATIONOF MYELOID PROGENITORS IN NORMAL BONE-MARROW CELLS

In the new context of the use of retinoic acid (RA) therapy as an indu cer of leukemic differentiation and a selective inhibitor of human mye loid leukemia cell growth, we undertook to explore the potential physi ological role of retinoids on the proliferation and differentiation of normal bone marrow myeloid progenitors. The effects of continuous exp osure of all-trans-RA, its naturally occurring isomer, 13-cis-RA, and its metabolite 4-oxo-all-trans-RA were studied on the growth of normal human bone marrow cells in soft agar, directly and after liquid cultu re. Retinoids enhanced the total number of granulocytic colony and mac rocluster formation in the presence of exogenous colony-stimulating fa ctor (n = 9). Dose-response curve were bell-shaped, with a maximal inc rement between concentration of 0.5 and 0.05 nm. In all cases, a conco mitant decrease of macrophagic colonies was noted. The positive effect on granulocytic colony formation was observed with each of the retino ids tested (all-trans, 13-cis and 4-oxo-all-trans) (n = 5). On erythro id colony formation, all-trans-RA had the opposite effect. Constant su ppression of CFU-E and BFU-E colony formation and coloring was observe d in a dose-related fashion from 0.1 to 10 muM (n = 5). Thus, in granu locytic, as in erythroid colony formation, retinoids affected both pro liferation and differentiation parameters. However, after short-term s uspension culture in the presence of all-trans-RA, an increase of both CFU-GM and BFU-E colonies, was observed. These results suggest a spec ific effect of retinoids on late myeloid precursors and places retinoi ds as possible candidates for enhancement of normal granulocytic diffe rentiation.