Suggested model of PML-RAR action in APL. (A) At 10⁻⁹ to 10⁻⁸ mol/L ATRA, PML-RAR prevents activation of key target genes required for myeloid differentiation by sequestration of RXR and other RAR cofactors, inhibiting normal RAR function. In addition, PML-RAR may bind to RAR targets as a homodimer or as a heterodimer with RXR and inhibit transcription of these genes by recruitment of corepressor/histone deacetlyase complexes. PML-RAR also may affect transcription mediated by AP1 and IFN-responsive factors and can sequester PLZF and potentially affect its function. PML-RAR prevents apoptosis through unknown mechanisms and delocalizes PML and other proteins from the nuclear body, although the importance of this is uncertain, because the NB is normal in the other forms of APL. (B) In the presence of pharmacological doses of ATRA, the PML-RAR fusion is degraded and releases PML and other cofactors. The NB structure is restored. A residual fragment of the PML-RAR fusion and/or the wild-type RAR, which is upregulated in response to ATRA, can then stimulate transcription of myeloid target genes. The blockade of other signaling pathways is released and the anti-apoptotic effect of PML-RAR is lost. As a result, terminal cell differentiation can proceed.