Induction of Erythroid Differentiation in K562 Cells by Inhibitors of Inosine Monophosphate Dehydrogenase

The effects of three inhibitors of inosine monophosphate (IMP) dehydrogenase on a human erythroleukemic cell line, K562, were studied. Following incubation with these inhibitors, K562 cells underwent differentiation and accumulated hemoglobins. The induction of hemoglobin accumulation was dose dependent; maximum induction was observed at 100, 25, and 3 μM, respectively, for ribavirin, tiazofurin, and mycophen-oiic acid. The induction was associated with reduction of intracellular GTP content and was blocked by adding guanosine within 24 h after adding inducer. The effective dose for half-maximum induction by ribavirin was 3 times less than that for 50% inhibition of K562 proliferation; however, for tiazofurin and mycophenolic acid, it closely approximated the concentrations which suppressed cellular proliferation. Ribavirin was sequestered preferentially inside the K562 cells, and the induction by ribavirin had a greater than 30-fold increase in hemoglobin. Studies with isoelectric focusing, globin chain analyses, and immunochemical assays indicated that both Aγ and Gγ were detected and that the hemoglobin produced in the ribavirin-treated cells consisted of approximately 60% fetal hemoglobin and its acetylated equivalents. The adult-type a globin was found, while no β globin chains were demonstrated. Thus, accumulation of fetal hemoglobin and production of a globin chain in ribavirin-treated cells are different from the pattern of hemoglobins induced by hemin.