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Extracellular ATP and CD39 Activate Camp-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia

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Extracellular ATP and CD39 Activate Camp-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia Published OnlineFirst July 8, 2020; DOI: 10.1158/2159-8290.CD-19-1008 RESEARCH ARTICLE Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia Nesrine Aroua1,2, Emeline Boet1,2, Margherita Ghisi1,2, Marie-Laure Nicolau-Travers1,2,3, Estelle Saland1,2, Ryan Gwilliam1,2, Fabienne de Toni1,2, Mohsen Hosseini1,2, Pierre-Luc Mouchel1,2,3, Thomas Farge1,2, Claudie Bosc1,2, Lucille Stuani1,2, Marie Sabatier1,2, Fetta Mazed4,5, Clément Larrue1,2, Latifa Jarrou1,2, Sarah Gandarillas6, Massimiliano Bardotti6, Muriel Picard2,7, Charlotte Syrykh1,2,8, Camille Laurent1,2,8, Mathilde Gotanègre1,2, Nathalie Bonnefoy9, Floriant Bellvert10, Jean-Charles Portais10, Nathalie Nicot11, Francisco Azuaje12, Tony Kaoma12, Carine Joffre1,2, Jérome Tamburini4,5, Christian Récher1,2,3, François Vergez1,2,3, and Jean-Emmanuel Sarry1,2 ABSTRACT Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell-surface expression and activity is increased in patients with AML upon chemotherapy compared with diagnosis, and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes cytarabine resist- ance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adap- tive mitochondrial stress response. Finally, genetic and pharmacologic inhibition of CD39 ecto-ATPase activity blocks the mitochondrial reprogramming triggered by cytarabine treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo. Together, these results reveal CD39 as a new residual disease marker and a promising therapeutic target to improve chemotherapy response in AML. SIGNIFICANCE: Extracellular ATP and CD39–P2RY13–cAMP–OxPHOS axis are key regulators of cyta- rabine resistance, offering a new promising therapeutic strategy in AML. 1Centre de Recherches en Cancérologie de Toulouse, UMR1037 Inserm/ Institute of Health, Luxembourg, Luxembourg. 12Computational Biomedi- Université Toulouse III-Paul Sabatier, ERL5294 CNRS, Equipe Label- cine Research Group, Quantitative Biology Unit, Luxembourg Institute of lisée LIGUE 2018, Toulouse, France. 2University of Toulouse, Toulouse, Health, Luxembourg, Luxembourg. 3 France. Service d’Hématologie, Institut Universitaire du Cancer de Note: Supplementary data for this article are available at Cancer Discovery 4 Toulouse-Oncopole, CHU de Toulouse, Toulouse, France. Institut Cochin, Online (http://cancerdiscovery.aacrjournals.org/). Département Développement, Reproduction, Cancer, UMR8104-CNRS, U1016-INSERM, Paris. 5Translational Research Centre in Onco-Hematology, N. Aroua, E. Boet, and M. Ghisi (listed in alphabetical order) share first Faculty of Medicine, University of Geneva, Geneva, Switzerland. 6Centre co–authorship of this article. Régional d’Exploration Fonctionnelle et Ressources Expérimentales, Ser- Corresponding Author: Jean-Emmanuel Sarry, Inserm, U1037, Centre de vice d’Expérimentation Animale, UMS006, Inserm, Toulouse, France. 7Inten- Recherches en Cancérologie de Toulouse, F-31024 Toulouse cedex 3, France. sive Care Unit, Institut Universitaire du Cancer de Toulouse-Oncopole, Phone: 335-8274-1632; Fax: 335-6274-4558; E-mail: jean-emmanuel. CHU de Toulouse, Toulouse, France. 8Service d’Anatomopathologie, Institut [email protected] Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, Cancer Discov 2020;10:1–22 France. 9Institut de Recherche en Cancérologie de Montpellier, U1194, Inserm, Université de Montpellier, Institut régional du Cancer de Mont- doi: 10.1158/2159-8290.CD-19-1008 pellier, Montpellier, France. 10TBI, Université de Toulouse, CNRS, INRA, ©2020 American Association for Cancer Research. INSA, Toulouse, France. 11LuxGene, Quantitative Biology Unit, Luxembourg OF1 | CANCER DISCOVERY OCTOBER 2020 AACRJournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst July 8, 2020; DOI: 10.1158/2159-8290.CD-19-1008 INTRODUCTION treatments eradicating RLCs and to improve the clinical outcome of these patients. Chemotherapy resistance is the major therapeutic barrier The biological basis of therapeutic resistance (drug efflux, in acute myeloid leukemia (AML), the most common acute detoxification enzymes, inaccessibility of the drug to the leu- leukemia in adults. AML is characterized by clonal expansion kemic niche) currently represents an active area of research. of immature myeloblasts and initiates from rare leukemic However, the molecular mechanisms underlying AML chemo- stem cells (LSC). Despite a high rate of complete remis- resistance are still poorly understood, especially in vivo. It is sion after conventional first-line induction chemotherapy nevertheless increasingly recognized that the causes of chemo- [e.g., daunorubicin or idarubicin plus cytarabine (AraC)], resistance and relapse reside within a small cell subpopula- the long-term prognosis is very poor for patients with AML. tion within the bulk of leukemic cells. Supporting this view, To date, the 5-year overall survival is still about 30% to 40% clinical studies have shown that the presence of high levels in patients younger than 60 years old and less than 20% in of CD34+CD38lo/−CD123+ cells at diagnosis correlates with patients older than 60. This results from the high frequency adverse outcome in patients with AML in terms of response of distant relapses (50% and 85% for patients younger and to therapy and overall survival (3, 4). Consistent with these older than 60 years of age, respectively) caused by tumor data, Ishikawa and colleagues (5) have observed that this pop- regrowth initiated by chemoresistant leukemic clones (RLC) ulation is also the most resistant to cytarabine treatment in and characterized by a refractory phase during which no vivo. As a first step toward successful therapeutic eradication other treatment has shown any efficacy thus far (1, 2). of these RLCs, it is now necessary to comprehensively profile Even with recent efficient targeted therapies that are FDA- the intrinsic and acquired characteristics of this cell popu- approved or under clinical development, therapy resistance lation. We have recently established a powerful preclinical remains the major therapeutic barrier in AML. Therefore, model to screen in vivo responses to conventional genotoxics understanding the molecular and cellular mechanisms driv- and to mimic the chemoresistance and minimal residual dis- ing chemoresistance is crucial for the development of new ease observed in patients with AML after chemotherapy (6). OCTOber 2020 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst July 8, 2020; DOI: 10.1158/2159-8290.CD-19-1008 RESEARCH ARTICLE Aroua et al. Accordingly, we have fully analyzed the response to chemo- also shown that high CD39-expressing resistant AML cells therapy of leukemic cells in AraC-treated AML patient-derived rely on an enhanced mitochondrial metabolism and are xenograft (PDX) mouse models. Surprisingly, we have found strongly dependent on the coordinated induction of cAMP- that cytarabine treatment equally kills both cycling and qui- PKA and ROS/ATF4 signaling downstream of CD39 to sur- escent cells and does not necessarily lead to LSC enrichment vive to chemotherapy. Accordingly, targeting CD39 markedly in vivo. However, we observed that cytarabine chemoresist- enhanced cytarabine cytotoxicity in AML cell lines and pri- ant leukemic cells exhibit elevated oxidative phosphorylation mary patient samples in vitro and in vivo through the inhibi- (OxPHOS) activity and that targeting mitochondrial oxida- tion of mitochondrial OxPHOS function, and this effect tive metabolism with OxPHOS inhibitors sensitizes resistant could be mimicked by inhibition of the PKA pathway. Over- AML cells to AraC (6, 7). Consistent with our findings, several all, this work shows that a key mechanism of resistance to groups have also demonstrated that essential mitochondrial AraC involves CD39-dependent cross-talk between the ener- functions contribute to resistance to multiple treatments in getic niche and leukemic mitochondrial functions through other cancer types (8–11). the CD39–P2RY13–cAMP–PKA axis in AML. Hyperleukocytosis is a clinical condition observed in patients with AML, which may lead to life-treatening com- RESULTS plications such as leukostasis and is associated with a higher risk of relapse. Importantly, this condition is sustained by Enhanced CD39/ENTPD1 Expression and several mediators of inflammation, which were also reported Activity Are Involved in Early Resistance to contribute to chemoresistance in AML (12–14). Support- to Cytarabine in AML ing this idea, a recent study reported that inhibition of the To identify new potential therapeutic targets involved in inflammatory chemoresistance pathway with dexamethasone the onset of cytarabine resistance in vivo, we analyzed a previ- improved outcome of patients with AML (15). In line with ously identified signature of 68 genes that are significantly these observations, recent work from our group (6) has high- upregulated in residual AML cells
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