A NOVEL RETINOIC ACID RECEPTOR (RAR)-SELECTIVE ANTAGONIST INHIBITS DIFFERENTIATION AND APOPTOSIS OF HL-60 CELLS - IMPLICATIONS OF RAR-ALPHA-MEDIATED SIGNALS IN MYELOID LEUKEMIC-CELLS

Retinoic acid (RA) induces HL-60 cells to differentiate terminally int o mature granulocytes, which subsequently die by apoptosis. The biolog ical effects of RA are mediated by two distinct families of transcript ion factors: retinoic acid receptors (RARs) and retinoid X receptors ( RXRs). RARs and RXRs form heterodimers and regulate retinoid-mediated gene expression. We have recently developed a novel RAR-selective anta gonist (ER27191) which prevents RAR activation by retinoids. Using thi s RAR-selective antagonist, and RXR and RAR agonist, we demonstrate th e RAR-mediated signaling pathway is important for differentiation and apoptosis of myeloid leukemic cells. Simple activation of RXRs is not sufficient to induce apoptosis of the cells. Interestingly, the combin ation of the RAR-selective antagonist and 9-cis RA resulted in partial differentiation and apoptosis of HL-60 and NB4 cells, whereas the RAR antagonist completely blocked all-trans RA-induced differentiation an d apoptosis of the cells. Additional experiments showed that levels of BCL-2 protein decreased during differentiation of myeloid leukemic ce lls. Furthermore, HL-60 cells transduced with a bcl-2 expression vecto r showed the same differentiation response to retinoids as did parenta l HL-60 cells even though apoptosis was inhibited in these bcl-2-trans duced cells, suggesting that differentiation and apoptosis are regulat ed independently in myeloid leukemic cells. (C) 1998 Elsevier Science Ltd. All rights reserved.