INHIBITORY-ACTION OF NM23 PROTEINS ON INDUCTION OF ERYTHROID-DIFFERENTIATION OF HUMAN LEUKEMIA-CELLS

We recently identified a differentiation inhibitory factor (I-factor) in mouse myeloid leukemia M1 cells as a murine homolog of the human nm 23-H2 gene product, nm23 genes encode proteins that participate in tum or metastasis regulation and in various fundamental cellular processes , although their mechanisms of action are still unknown. Although all nm23 proteins contain nucleoside diphosphate (NDP) kinase activity, it has not been established that the enzyme activity mediated the variou s functions of nm23 proteins. In the present experiment, we examined t he effect of nm23 proteins on various differentiation induction system s of human leukemic cells including HL-60, U937, HEL/S, KU812F, K562, and HEL cells. Native human erythrocyte NDP kinase protein inhibited t he induction of erythroid differentiation of HEL, KU812 and K567 cells , but not the induction of monocytic or granulocytic differentiation o f HL-60, U937 and HEL/S cells. The erythroid differentiation of HEL ce lls was inhibited by recombinant human nm23-H1, -H2, mouse nm23-M1, an d -M2 proteins. Moreover, both the mutant nm23-H2(His) protein and tru ncated nm23-H2 protein containing N-terminal (1-60) peptide, which do not have NDP kinase activity, also inhibited erythroid differentiation of HEL cells. These results suggest that (1) the differentiation inhi bitory activity of I-factor/nm23 protein is not restricted to monocyti c differentiation of M1 cells, (2) the inhibitory activity is exhibite d without species specificity, and (3) the differentiation inhibitory activity of the nm23/NDP kinase protein is independent of its enzyme a ctivity and requires the presence of N-terminal peptides.