New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor α Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation

Cassinat, Bruno; Zassadowski, Fabien; Ferry, Christine; Llopis, Laura; Bruck, Nathalie; Lainey, Élodie; Duong, Vanessa; Cras, Audrey; Despouy, Gilles; Chourbagi, Oussama; Beinse, Guillaume; Fenaux, Pierre; Egly, C. Rochette; Chomienne, Christine

doi:10.1128/mcb.00756-10

Cited by 23 publications

(24 citation statements)

References 43 publications

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“…50 In contrast with this proposal, our observations of terminal differentiation upon RXR excision do not favor a model in which transcriptional reactivation by RARA/RXRA is essential for differentiation (Figure 6). PML/RARA degradation is essential to loss of self-renewal, whereas direct transcriptional activation is believed to trigger APL differentiation.…”

Section: Discussioncontrasting

confidence: 54%

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

Vitaliano-Prunier

Halftermeyer

Ablain

et al. 2014

Blood

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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...

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Section: Discussioncontrasting

confidence: 54%

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

Vitaliano-Prunier

Halftermeyer

Ablain

et al. 2014

Blood

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“…58 Furthermore, ATRA recruits RARa to the regulatory regions of target genes, while it releases PML-RARa from the same binding sites. 13 An increased RARa/PML-RARa ratio may diminish the suppressive effects of PML-RARa on common retinoid target genes involved in differentiation and/or growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Immunoprecipitated DNA was amplified by quantitative PCR using a Light Cycler realtime PCR system (Roche Applied Science, Ltd, Monza, Italy). 13,20 Occupancy of the promoters was calculated by normalizing the PCR signals from the IP samples to the signals obtained from the input DNA. The specificity of the experimental conditions was checked in the absence of antibodies, with isotype-matched control IgG and with the promoter of a control 36BA gene.…”

Section: Nb4mentioning

confidence: 99%

p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells

et al. 2012

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All-trans retinoic acid (ATRA) is the only clinically useful differentiating agent, being used in the treatment of acute promyelocytic leukemia (APL). The use of ATRA in other types of acute myelogenous leukemia (AML) calls for the identification of novel strategies aimed at increasing its therapeutic activity. Here, we provide evidence that pharmacological inhibition of the mitogen-activated protein kinase, p38a, or silencing of the corresponding gene sensitizes APL and AML cell lines, as well as primary cultures of AML blasts to the anti-proliferative and cyto-differentiating activity of ATRA and synthetic retinoids. P38a inhibits ligand-dependent transactivation of the nuclear retinoic acid receptor, RARa, and the derived chimeric protein expressed in the majority of APL cases, PML-RARa. Inhibition is the consequence of ligand-independent binding of p38a, which results in stabilization of RARa and PML-RARa via blockade of their constitutive degradation by the proteasome. The inhibitory effect requires a catalytically active p38a and direct physical interaction with RARa and PML-RARa. Ser-369 in the E-region of RARa is essential for the binding of p38a and the ensuing functional effects on the activity of the receptor.

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“…Restoration of the RAR promoter permissiveness and leukemic differentiation was achieved by activating the MEK/ERK signaling pathway through G-CSF receptor activation (13). In other cell types, the regulation by post-translational modification of nuclear receptors (NRs) after intracellular signaling activation has been well described (14).…”

Section: Introductionmentioning

confidence: 99%

Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

et al. 2015

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We recently identified that the MEK/ERK1/2 pathway synergized with retinoic acid (RA) to restore both transcriptional activity and RA-induced differentiation in RA-resistant acute promyelocytic leukemia (APL) cells. To target the MEK/ERK pathway, we identified glycogen synthase kinase-3β (GSK-3β) inhibitors including lithium chloride (LiCl) as activators of this pathway in APL cells. Using NB4 (RA-sensitive) and UF-1 (RA-resistant) APL cell lines, we observed that LiCl as well as synthetic GSK-3β inhibitors decreased proliferation, induced apoptosis and restored, in RA-resistant cells, the expression of RA target genes and the RA-induced differentiation. Inhibition of the MEK/ERK1/2 pathway abolished these effects. These results were corroborated in primary APL patient cells and translated in vivo using an APL preclinical mouse model in which LiCl given alone was as efficient as RA in increasing survival of leukemic mice compared with untreated mice. When LiCl was combined with RA, we observed a significant survival advantage compared with mice treated by RA alone. In this work, we demonstrate that LiCl, a well-tolerated agent in humans, has antileukemic activity in APL and that it has the potential to restore RA-induced transcriptional activation and differentiation in RA-resistant APL cells in an MEK/ERK-dependent manner.

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New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor α Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation

Cited by 23 publications

References 43 publications

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

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

p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells

Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

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