The impact of differential binding of wild-type RAR alpha, PML-, PLZF- andNPM-RAR alpha fusion proteins towards transcriptional co-activator, RIP-140, on retinoic acid responses in acute promyelocytic leukemia

Retinoic acid receptor (RA) heterodimer (RAR/RXR) activities have been show n to be repressed by transcriptional corepressor, SMRT/N-CoR, in the absenc e of the ligand while upon all-trans retionic acid (ATRA) treatment, SMRT/N -CoR is dissociated from RAR alpha leading to gene expression by the recrui tment of transcriptional co-activators to the transcriptional complex. The difference in response to ATRA therapy between acute promyelocytic leukemia (APL) patients with PML-RAR alpha fusion and PLZF-RAR alpha fusion has rec ently been found to be partially due to the strong association of the trans criptional co-repressor, SMRT/N-CoR, with PLZF domain. We demonstrate that SMRT association, as with PML-RAR alpha, can be released from NPM-RAR alpha at pharmacological concentration of ATRA (10(-6) hn), Moreover, we show fo r the first time that the interaction between the transcriptional co-activa tor, RIP-140, and PML-, PLZF- or NPM-RAR alpha fusion proteins can be posit ively stimulated by ATRA although they are less sensitive as compared with the wild-type RAR alpha, Our results suggest that the dissociation of trans criptional co-repressors, SMRT/N-CoR, and recruitment of co-activators, eg RIP-140, to APL-associated fusion proteins constitute a common molecular me chanism in APL and underlie the responsiveness of the disease to RA therapy .