Growth inhibition of human acute promyelocytic leukemia NB-4 cells by interferons and all-trans retinoic acid: trans-modulation of inducible gene expression pathways.

Regulation of cell proliferation appears to be a complex process involving the regulated expression and/or interaction of gene regulatory pathways stimulated by binding of specific growth regulators such as inteferons (IFN) and all-trans retinoic acid (RA) to their respective receptors. We investigated the growth regulation of human acute promyelocytic leukemia NB-4 cells by combinations of IFNs and RA, and explored the possible biochemical interactions between IFNs and RA by studying the regulation of expression of IFN- and RA-inducible cellular pathways by RA and IFN respectively. We observed that combinations of IFNs and RA inhibited NB-4 cell growth significantly more than either agent alone. Analysis of cellular inducible pathways demonstrated that RA augmented 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 such as mRNA 1-8. Furthermore, IFNs also augmented the expression 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 not induced by either IFN-gamma or RA alone. These results suggest that gene inducing interactions, the transregulation of IFN-inducible and RA-inducible gene expression pathways by RA and IFNs, respectively, may be closely related to the potentiation of growth inhibition of NB-4 cells by combinations of IFNs and RA. These findings may be useful in establishing a rationale for using IFNs and RA or combinations of IFNs and RA in the treatment of acute promyelocytic leukemia.