Model for the role of nuclear receptor corepressor N-CoR/Sin3A/HDAC1 complex and RARα fusion proteins in the pathogenesis and treatment of APL. (A) In the absence of ATRA, RARα, PML-RARα, and PLZF-RARα associate with N-CoR/Sin3A/HDAC1 corepressor complex. The associated corepressor/RARα complex acts on chromatin structure by deacetylation of histone tails inducing its reorganization into a repressed state that is inaccessible to basal transcription factors. Binding of ATRA (orange triangle) induces conformational change in the RARα, causing dissociation of the corepressor complex and association of a coactivator, such as SRC-1, with intrinsic histone acetyltransferase activity.76Acetylation (Ac) of histone tails disrupts tightly packed and repressed chromatin structure, allowing access of the basal transcription factors and transcriptional activation. Physiologic concentrations of ATRA (10−8) are sufficient to induce this process. (B) In the case of the PML-RARα protein, pharmacologic doses of ATRA (10−6 mol/L) are required to achieve efficient dissociation of the N-CoR corepressor complex from the chimeric protein and transcriptional activation. (C) Because of additional, ligand-insensitive interactions between the PLZF moiety of the PLZF-RARα fusion protein and N-CoR (and possibly also Sin3A and HDAC1), the corepressor/PLZF-RARα complex remains associated even in the presence of pharmacologic concentrations of ATRA and, in the absence of chromatin remodelling by histone acetylation, transcription remains inhibited.
