ALL-TRANS AND 9-CIS RETINOIC ACID ENHANCE 1,25-DIHYDROXYVITAMIN-D-3-INDUCED MONOCYTIC DIFFERENTIATION OF U937 CELLS

Retinoic acid (RA) and 1,25-dihydroxyvitamin D-3 (D-3) are well known for inducing differentiation in many leukemic cell lines. The nuclear signalling pathways of RA and D-3 are mediated through their cognate r eceptors, the retinoic acid receptor (RAR) and vitamin D-3 receptor (V DR), respectively. Retinoid X receptor (RXR) is an auxiliary factor th at forms a heterodimer with RAR and VDR, enabling their efficient tran scriptional activation. 9-cis RA, a high-affinity ligand for RXR, grea tly enhanced D-3-induced CD14 expression in U937 cells, while RA alone did not induce CD14 expression. 9-cis RA also resulted in morphologic al changes of U937 cells to macrophage-like cells when combined with D -3, while RA alone resulted in granulocyte-like cells. RA and D-3 toge ther enhanced c-fms expression, phagocytic activity, and acted synergi stically to promote nitroblue tetrazolium reduction activity and inhib it proliferation. Northern analysis showed that U937 cells constitutiv ely expressed RAR-alpha, VDR and RXR-alpha mRNAs. RA or D-3 alone or i n combination did not affect RAR-alpha and VDR expression, while 9-cis RA and 9-cis RA plus all-trans RA significantly reduced RXR-alpha exp ression. Interestingly, D-3 could restore the down-regulation of RXR-a lpha mRNA by 9-cis RA. These findings suggest that there is crossover of the nuclear signalling pathways of RA and D-3. This may have clinic al implications in that RA and D-3 may be used in combination for diff erentiation-inducing therapy in acute myelogenous leukemia and myelody splastic syndrome. Copyright (C) 1996 Elsevier Science Ltd.