GROWTH-INHIBITION OF HUMAN ACUTE PROMYELOCYTIC LEUKEMIA NB-4 CELLS BYINTERFERONS AND ALL-TRANS-RETINOIC ACID - TRANS-MODULATION OF INDUCIBLE GENE-EXPRESSION PATHWAYS

Regulation of cell proliferation appears to be a complex process invol ving the regulated expression and/or interaction of gene regulatory pa thways stimulated by binding of specific growth regulators suck as int erferons (IFN) and all-trans retinoic acid (RA) to their respective re ceptors. We investigated the growth regulation of human acute promyelo cytic leukemia NB-4 cells by combinations of IFNs and RA, non explored the possible biochemical intel actions between IFNs and RA by studing the regulation of expression of IFN- and RA-inducible cellular pathwa ys by RA and IFN respectively. We observed that combinations of IFNs a nd RA inhibited NB-4 cell growth significantly more than either agent alone. Analysis of cellular inducible pathways demonstrated that RA au gmented levels of gene expression: (i) induced by IFN-alpha such as 2' -5'-oligoadenylate synthetase, mRNA 561 and mRNA 6-16; (ii) induced by IFN-gamma such as 2A and P56; and (iii) induced by both IFN-alpha and IFN-gamma arch as mRNA 1-8. Furthermore, IFNs also augmented the expr ession of RAR-alpha mRNA and RAR-alpha. Co-treatment of NB-4 cells by IFN-gamma plus RA induced a sub-set of IFN-induced genes which were no t induced by either IFN-gamma ol RA alone. These results suggest that gene inducing interactions, the transregulation of IFN-inducible and R A-inducible gene expression pathways by RA and IFNs, respectively, may be closely related to the potentiation of growth inhibition of NB-4 c ells by combinations of IFNs and RA. These findings may be useful in e stablishing a rationale for using IFNs and RA ol combinations of IFNs and RA in the treatment of acute promyelocytic leukemia.