EFFECTS OF NOVEL RETINOID X RECEPTOR-SELECTIVE LIGANDS ON MYELOID LEUKEMIC DIFFERENTIATION AND PROLIFERATION IN-VITRO

The biologic effects of retinoids such as all-trans-retinoic acid (ATR A) and g-cis-retinoic acid on proliferation and differentiation of hem atopoietic cells are mediated by binding and activating two distinct f amilies of transcription factors: the retinoic acid receptors (RARs) a nd the retinoid X receptors (RXRs). The RARs require heterodimerizatio n with RXRs; in addition, RXRs can form homodimers, which can bind to DNA response elements that are either distinct or the same as those bo und by the RAR/RXR heterodimers. Therefore, the two retinoid pathways provide sequences that are specific for effective DNA binding and acti vation of target genes. We have developed several series of novel synt hetic retinoids that selectively interact with RXR/RXR homodimers and RAR/RXR heterodimers. We show here that SR11236 and SR11246, which are RXR-selective analogs, had little ability to inhibit clonal growth an d induce differentiation of leukemic cells (HL-60 cells and fresh acut e myeloid leukemia cells). However, SR11249, SR11256, and LGD1069, whi ch activated both RXR/RXR homodimers and RAR/RXR heterodimers, could i nhibit clonal growth and induce differentiation of HL-60 cells as well as leukemic cells from patients, including those with acute promyeloc ytic leukemia (APL). This is similar to results observed with RAR/RXR- specific ligands. Interestingly, the combination of ATRA and either SR 11249. SR11256, or LGD1069 showed synergistic effects in inducing diff erentiation of HL-60 cells. A retinoid (SR11238) with strong anti-AP-1 activity that did not activate the RARs and RXRs for gene transcripti on from the response element TREpal was inactive in our assay systems, suggesting that the antiproliferative effects of retinoids on leukemi c cells is not mediated by inhibiting the AP-1 pathway. We conclude th at the RAR/RXR pathway is more important than RXR/RXR pathway for diff erentiation and proliferation of acute myeloid leukemic cells, and cer tain retinoids or combination of retinoids with both RAR and RXR speci ficities may synergistically enhance the differentiation activity of A TRA, which may be relevant in several clinical situations. (C) 1996 by The American Society of Hematology.