Historical model of PML-RARA-mediated transcriptional repression, RA-induced activation, and differentiation therapy. In the nucleus of APL cells, PML-RARA forms dimers through the coiled-coil domain of PML and binds DNA via its RARA moiety. The complex tightly associates with corepressors, resulting in transcriptional repression of target genes and in differentiation arrest. On exposure to pharmacologic doses of RA, PML-RARA switches to an active conformation and the corepressors are replaced by coactivators, thus enforcing the transcription of target genes, triggering the differentiation process and ultimately leading to cure.