APL is driven by a PML/RARA fusion that enhances self-renewal of clonogenic progenitors and blocks promyelocytes differentiation. PML/RARA binds RXR, Daxx and corepressors. Retinoic acid promotes differentiation through transcriptional activation and PML/RARA degradation by the proteasome. Arsenic primarily degrades PML/RARA, through sumoylation of its PML moiety and subsequent ubiquitination. Oncogene degradation affects self-renewal of the progenitors and tightly correlates with disease clearance and cure. For further details, please see Nasr and coworkers 6321 in this issue.