differentiation Clearance of PML/RARA-bound promoters suffice to initiate APL

Abstract PML/RARA, a potent transcriptional inhibitor of nuclear receptor signaling, represses myeloid differentiation genes and drives acute promyelocytic leukemia (APL). Association of the RXRA co-receptor to PML/RARA is required for transformation, RXRA promoting its efficient DNA-binding. APL is exquisitely sensitive to retinoic acid (RA) and arsenic trioxide (arsenic), which both trigger cell differentiation . While RA elicits in vivotranscriptional activation of PML/RARA targets, how arsenic triggers differentiation remains unclear. Here we demonstrate that extinction of PML/RARA triggers terminal differentiation in vivo . Similarly, ablation of RXRs loosens PML/RARA DNA-binding, inducing terminal differentiation of APL cells ex vivo or in vivo . RXRA sumoylation also directly contributes to PML/RARA-dependent transformation , presumably by enhancing transcriptional ex vivorepression. Thus, APL differentiation is a default program triggered by clearance of PML/RARA-bound promoters, rather than obligatory active transcriptional activation, explaining how arsenic elicits APL maturation through PML/RARA degradation.