Synergistic action of activin A and hexamethylene bisacetamide in differentiation of murine erythroleukemia cells.

Activin A, a peptide homologous to transforming growth factor beta, induced erythroid differentiation of murine erythroleukemia cells in a dose-dependent manner, as judged by the proportion of benzidine-positive cells. The extent of differentiation induced by activin A depended on the cell density in the initial inoculum; the percentage of benzidine-positive cells markedly decreased at an increasing cell density. In contrast, the hexamethylene bisacetamide (HMBA)-induced differentiation was affected only to a little extent by the cell density. Furthermore, the effects of activin A and HMBA were different in sensitivity to the inhibition by dexamethasone; the HMBA-induced differentiation was reduced by about 90% in the presence of dexamethasone, whereas the activin A-induced differentiation was reduced by 40 to 50%. Activin A and HMBA induced the differentiation in a synergistic manner. Especially when the maximal response to activin A was suppressed at high cell density, the simultaneous presence of a suboptimal concentration of HMBA markedly recovered this suppression. This synergism seemed to be generated at the commitment process. Taken together, these results indicate that activin A and HMBA exert their actions, at least in part, through different pathways, and that these pathways interact with each other, resulting in synergistic induction of murine erythroleukemia cell differentiation. Clinical implications of these findings are discussed.