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

Abstract

Key Points• PML/RARA loss or detachment from target promoters suffices to differentiate APL cells.• PML/RARA degradation by arsenic thus explains arsenicinduced differentiation.PML/RARA, a potent transcriptional inhibitor of nuclear receptor signaling, represses myeloid differentiation genes and drives acute promyelocytic leukemia (APL). Association of the retinoid X receptor-a (RXRA) coreceptor to PML/RARA is required for transformation, with RXRA promoting its efficient DNA binding. APL is exquisitely sensitive to retinoic acid (RA) and arsenic trioxide (arsenic), which both trigger cell differentiation in vivo. Whereas RA elicits transcriptional 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 retinoid X receptors loosens PML/RARA DNA binding, inducing terminal differentiation of APL cells ex vivo or in vivo. RXRA sumoylation directly contributes to PML/RARA-dependent transformation ex vivo, presumably by enhancing transcriptional repression. 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. (Blood. 2014;124(25):3772-3780) IntroductionAcute promyelocytic leukemia (APL) is characterized by gene fusions involving retinoic acid receptor-a (RARA) gene. The most common t(15;17) translocation fuses PML to RARA, yielding the PML/RARA fusion oncoprotein. PML, the key organizer of nuclear bodies (NB), is involved in redox sensing and hence confers sensitivity to arsenic.1-3 PML/RARA is a potent transcriptional repressor of retinoic acid (RA) signaling that interferes with gene expression programs involved in both hematopoietic progenitor selfrenewal and terminal myeloid cell differentiation. 4,5 Treatment of APL patients with RA induces terminal differentiation and transient remissions. Mechanistically, this is believed to reflect transcriptional reactivation of PML/RARA-silenced genes by RA, the ligand for RARA and PML/RARA, 6 whereas RA-triggered PML/RARA degradation accounts for loss of self-renewal. 7,8 Arsenic definitively cures a substantial proportion of patients as a single agent. [9][10][11] Ex vivo studies have demonstrated that arsenic primarily induces apoptosis of APL cells, 12 although subsequent studies demonstrated partial and complete differentiation ex vivo and in vivo, respectively. 13Molecularly, arsenic degrades PML/RARA but otherwise does not directly affect transcriptional regulation by RARA, raising the issue of the basis for differentiation.14,15 Arsenic also acts on normal PML to promote loss of self-renewal, likely explaining its clinical potency. 7,16 In normal cells, RARA is always associated with retinoid X receptors (RXRs) the universal partners of type II nuclear receptors to bind their responsive elements. RA binds to retinoic acid receptors (RARs), in...

Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells

“…15,30,31 The results obtained here with NPM1 mutant AML unexpectedly bear some similarities with APL. First, mutant NPM1 is degraded with RA or arsenic exposure, and p53 signaling is activated.…”

p53 as an Effector or Inhibitor of Therapy Response

“…Studies performed in mouse models of APL have conclusively shown that PML/RARA loss is responsible for the abrogation of APL self-renewal Ablain et al 2013Ablain et al , 2014. Subsequent studies showed that PML/RARA loss is actually sufficient for differentiation, thus explaining in vivo myeloid maturation on arsenic exposure (Vitaliano-Prunier et al 2014).…”

RXRα ligand Z-10 induces PML-RARα cleavage and APL cell apoptosis through disrupting PML-RARα/RXRα complex in a cAMP-independent manner

“…RXRα has been shown to be required for PML-RARα sumoylation and efficiently binding to DNA, both of which are essential events for APL transformation [22, 23]. In our research, we unraveled that RXRα was also vital for the stability of PML-RARα (Figure 3), which provided a new mechanism underlying RXRα actions in APL.…”

“…In the heterotetramer, PML-RARα not only interacts with RXRα through RARα moiety, but also interacts with each other through PML moiety [23, 25]. These may underlie the different modes of RXRα interaction with PML-RARα and RARα.…”