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Classic and Variants Apls, As Viewed from a Therapy Response

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Classic and Variants Apls, As Viewed from a Therapy Response cancers Review Classic and Variants APLs, as Viewed from a Therapy Response Marie-Claude Geoffroy 1,2,3 and Hugues de Thé 1,2,3,4,5,* 1 Institut National de la Santé et de la Recherche Médicale (INSERM) U944, Equipe Labellisée par la Ligue Nationale contre le Cancer, 75010 Paris, France; marie-claude.geoff[email protected] 2 Centre National de la Recherche Scientifique Unité Mixte de Recherche 7212, Institut Universitaire d'Hématologie (IUH), 75010 Paris, France 3 Institut de Recherche Saint-Louis, Université de Paris, 75010 Paris, France 4 Assistance Publique-Hôpitaux de Paris, Service de Biochimie, Hôpital St-Louis, 75010 Paris, France 5 Collège de France, PSL Research University, INSERM U1050, CNRS UMR 7241, 75005 Paris, France * Correspondence: [email protected] Received: 24 March 2020; Accepted: 9 April 2020; Published: 14 April 2020 Abstract: Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of “classic” APL pathogenesis and therapy response. Keywords: leukemia; retinoic acid signaling; ATRA; ATO; PML; targeted therapy 1. Introduction Acute promyelocytic leukemia (APL) accounts for 10–15% of all acute myeloid leukemias (AML) with an annual incidence estimated at 0.0001% in Europe [1]. APL is a unique subtype of AML in which immature promyelocytes abnormally proliferate into the bone marrow. Classic APL is driven by a specific chromosomal translocation leading to the formation of PML-RARA, an oncogenic fusion protein found in over 98% of APL patients [2–5]. The resulting chimeric PML-RARA protein (Figure1) promotes a clonal proliferation of myeloid precursors with a reduced differentiation capacity and acquisition of self-renewal. Pathogenesis of these “classic” APLs has been extensively reviewed elsewhere [6–8] and will only be sketched here. The World Health Organization (WHO) has revised the classification of AMLs, making APL with t(15; 17) (q24.1; q21.2), as a specific entity, but without taking in account the novel PML-independent RARs fusions [9]. Indeed, some other translocations driving the formation of fusion proteins have been described in very rare forms of leukemia with features of APL. While the genetics of these novel variant APL-like syndromes is now quite well delineated, their pathogenesis remains puzzling and treatment outcomes generally poor. Here, we review and put in perspective this recent literature on current understanding of genetic, pathogenesis and therapy response for these non “classic” APLs, stressing the role of global deregulated retinoic acid signaling in their pathogenesis. Cancers 2020, 12, 967; doi:10.3390/cancers12040967 www.mdpi.com/journal/cancers Cancers 2020, 12, 967 2 of 22 Cancers 2020, 12, x 2 of 22 FigureFigure 1. 1.Structural Structural organization organization of of PML-RARA PML-RARA and and other other PML-independent PML-independent RAR RAR fusions fusions in in acute acute promyelocyticpromyelocytic leukemia leukemia (APL) (APL cells.) cells. SchematicSchematic representationsrepresentations ofof PML PML (isoform (isoform I), I), RARA RARA and and fusionfusion partners partners of of other other retinoic retinoic acid acid receptors receptors (RARB (RARB and and RARG) RARG) before before and and after after chromosomal chromosomal rearrangements.rearrangements. Exons Exons are are shown shown in in blue. blue. The The frequency frequency of of breakpoint breakpoint cluster cluster regions regions (Bcr) (Bcr) in in APL APL isis indicated indicated in in a percentagea percentage and and fusion fusion points points are are represented represented by by a a red red arrow. arrow. The The RING RING finger finger (R), (R), B-boxesB-boxes (B1 (B1 and and B2), B2), coiled-coil coiled-coil domain domain (CC), (CC), nuclear nuclear signal signal (nls) (nls) and and sumo-interactif sumo-interactif motif motif (SIM) (SIM) in in PMLPML are are represented represented by by di differentfferent colored colored boxes boxes as as well well as as functional functional domains domains in in RARA: RARA: A-B: A-B: AF-1 AF-1 transcriptionaltranscriptional domain; domain; C: C: DNA DNA binding binding domain domain (DBD); (DBD); D: D: hinge hinge region; region; E: E: ligand ligand binding binding domain domain (LBD), heterodimerization and AF-2 transactivation domain; F: unknown function. (LBD), heterodimerization and AF-2 transactivation domain; F: unknown function. 2. Current Understanding of Classic APL Pathogenesis and Treatment Response 2. Current Understanding of Classic APL Pathogenesis and Treatment Response Pathogenesis of “classic” APLs was extensively reviewed elsewhere and will be only briefly summarizedPathogenesis here. Fusion of “classic” of PML APLs to RARA was yields extensively an oncogenic reviewed transcription elsewhere factor, and whichwill be triggers only briefly both transcriptionalsummarized here. deregulation Fusion of of PML RARA to andRARA non-RARA yields an target oncogenic genes, transcription together with factor disruption, which of triggers PML nuclearboth transcriptional bodies, the key deregulation regulators of of senescence RARA and [10 non–12-RAR]. MultipleA target other genes features, together of PML-RARA with disruption were of described,PML nuclear but their bodies actual, the contributions key regulators to in of vivo senescenc transformatione [10–12] remains. Multiple unestablished. other features One of of PML the - mostRARA striking were features described, of APL but is itstheir sensitivity actual to targetedcontributions therapies to [in6]. Indeed,vivo transformation APL has now becomeremains theunestablished most curable. One form of of the adult most leukemia striking when features treated of APL by combined is its sensitivity therapies to withtargeted all trans-retinoic therapies [6]. acidIndeed, (ATRA) APL and has arsenic now become trioxide the (ATO). most Clinical curable management form of adult of APLleukemia has been when recently treated reviewed by combined [13]. Majortherapies therapeutic with all advances trans-retinoic were obtained acid (ATRA) in the and ‘90s arsenic with the trioxide introduction (ATO). of Cli diffnicalerentiation manag therapyement of withAPL ATRA has been [14]. recently To avoid reviewed relapse that [13] almost. Major invariably therapeutic occurs advances with were ATRA obtained monotherapy, in the ‘90s ATRA with plus the anthracycline-basedintroduction of differentiation chemotherapy therapy became with the standardATRA [14] treatment. To avoid for APLrelapse with that complete almostremission invariably ratesoccurs to 90–95%,with ATRA but delayed monotherapy, relapses occurredATRA plus in many anthracycline patients. First-based line chemotherapy administration became of ATO inthe combinationstandard treatment with ATRA for radically APL with changed complete the prognosisremission of rates a fatal to disease 90–95%, into but a fully delayed curable relapses one, evenoccurred without in many chemotherapy patients. [First15–18 line]. The administration urgent necessity of ATO to make in combination ATO available with in ATRA all countries, radically changed the prognosis of a fatal disease into a fully curable one, even without chemotherapy [15– in particular the oral form, which has proven its clinical utility in multiple trials, should be stressed in that18] respect. The urgent [19,20 necessity]. to make ATO available in all countries, in particular the oral form, which has proven its clinical utility in multiple trials, should be stressed in that respect [19,20]. ATRA acts at the transcriptional level to de-repress RARA target genes, yielding terminal differentiationATRA acts of malignant at the transcriptional promyelocytes level into matureto de-repress granulocytes RARA [ 21target]. Mechanistically, genes, yielding binding terminal of differentiation of malignant promyelocytes into mature granulocytes [21]. Mechanistically, binding ATRA to the RARA moiety of PML-RARA induces a conformational change that causes the dissociation of ATRA to the RARA moiety of PML-RARA induces a conformational change that causes the of corepressors complexes and the recruitment of coactivators, activating gene re-expression. ATRA also dissociation of corepressors complexes and the recruitment of coactivators, activating gene re- expression. ATRA also acts on the stability of the PML-RARA protein by inducing its degradation Cancers 2020, 12, 967 3 of 22 acts on the stability of the PML-RARA protein by inducing its degradation in a proteasome-dependent manner, but also through proteolytic cleavage and autophagy-dependent mechanisms [22–24]. PML-RARA degradation per se results in the transcriptional reactivation of many differentiation genes, together with the reformation of PML nuclear bodies [25,26]. Arsenic binds directly onto specific
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