A system biology model of the molecular mechanisms involved in APL. (A) In the absence of treatment, PML-RARA homodimers associated with RXR bind to specific sequences in the promoter region of target genes. The bound DNA sequences are either RARA-binding sequences (eg, DR5) or more relaxed repeat motifs (referred to as DRX). The direct or indirect regulation of target genes is responsible for the differentiation block, aberrant self-renewal, and impairment of apoptosis observed in APL blasts. (B) On RA treatment, PML-RARA activates the transcription of target genes. One may also propose that PML-RARA degradation by RA allows RARA-binding to DR5-containing promoters. (C) Arsenic triggers PML-RARA degradation, resulting in the derepression of specific PML-RARA target genes (with DRX-containing promoters), whereas RARA can replace PML-RARA on DR5 sequences. The differential modulation of these 2 subsets of target genes by RA or arsenic may account for the different cellular aspects of response in vivo.