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

Nesrine Aroua; Emeline Boet; Margherita Ghisi; Marie-Laure Nicolau-Travers; Estelle Saland; Ryan Gwilliam; Fabienne de Toni; Mohsen Hosseini; Pierre-Luc Mouchel; Thomas Farge; Claudie Bosc; Lucille Stuani; Marie Sabatier; Fetta Mazed; Clément Larrue; Latifa Jarrou; Sarah Gandarillas; Massimiliano Bardotti; Muriel Picard; Charlotte Syrykh; Camille Laurent; Mathilde Gotanègre; Nathalie Bonnefoy; Floriant Bellvert; Jean-Charles Portais; Nathalie Nicot; Francisco Azuaje; Tony Kaoma; Carine Joffre; Jérome Tamburini; Christian Récher; François Vergez; Jean-Emmanuel Sarry

doi:10.1158/2159-8290.CD-19-1008

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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

Nesrine Aroua, Emeline Boet, Margherita Ghisi, Marie-Laure Nicolau-Travers, Estelle Saland, Ryan Gwilliam, Fabienne de Toni, Mohsen Hosseini, Pierre-Luc Mouchel, Thomas Farge, …

Cancer Discovery, Vol.10(10), pp.1544-1565

01/10/2020

DOI: https://doi.org/10.1158/2159-8290.CD-19-1008

PMID: 32641297

Résumé

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 resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated adaptive 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.

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Titre: Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia
Créateurs - sans rôle: Nesrine Aroua - Institut universitaire du cancer de Toulouse Oncopole
Emeline Boet - Institut universitaire du cancer de Toulouse Oncopole
Margherita Ghisi - Institut universitaire du cancer de Toulouse Oncopole
Marie-Laure Nicolau-Travers - Institut universitaire du cancer de Toulouse Oncopole
Estelle Saland - Institut universitaire du cancer de Toulouse Oncopole
Ryan Gwilliam - Institut universitaire du cancer de Toulouse Oncopole
Fabienne de Toni - Institut universitaire du cancer de Toulouse Oncopole
Mohsen Hosseini - Institut universitaire du cancer de Toulouse Oncopole
Pierre-Luc Mouchel - Institut universitaire du cancer de Toulouse Oncopole
Thomas Farge - Institut universitaire du cancer de Toulouse Oncopole
Claudie Bosc - Institut universitaire du cancer de Toulouse Oncopole
Lucille Stuani - Institut universitaire du cancer de Toulouse Oncopole
Marie Sabatier - Institut universitaire du cancer de Toulouse Oncopole
Fetta Mazed - Institut Cochin
Clément Larrue - Institut universitaire du cancer de Toulouse Oncopole
Latifa Jarrou - Institut universitaire du cancer de Toulouse Oncopole
Sarah Gandarillas - Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales
Massimiliano Bardotti - Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales
Muriel Picard - Pôle Anesthésie Réanimation [CHU de Toulouse]
Charlotte Syrykh - Institut universitaire du cancer de Toulouse Oncopole
Camille Laurent - Institut universitaire du cancer de Toulouse Oncopole
Mathilde Gotanègre - Institut universitaire du cancer de Toulouse Oncopole
Nathalie Bonnefoy - Université de Montpellier, Institut de Recherche en Cancérologie de Montpellier - IRCM
Floriant Bellvert - Toulouse Biotechnology Institute
Jean-Charles Portais - Toulouse Biotechnology Institute
Nathalie Nicot - Luxembourg Institute of Health
Francisco Azuaje - Luxembourg Institute of Health
Tony Kaoma - Luxembourg Institute of Health
Carine Joffre - Institut universitaire du cancer de Toulouse Oncopole
Jérome Tamburini - Institut Cochin
Christian Récher - Institut universitaire du cancer de Toulouse Oncopole
François Vergez - Institut universitaire du cancer de Toulouse Oncopole
Jean-Emmanuel Sarry - Institut universitaire du cancer de Toulouse Oncopole
Détails de publication: Cancer Discovery, Vol.10(10), pp.1544-1565
Note de subvention: Canceropole GSO 2014-E07
Identifiants: 99160966209311
Unité académique: Institut de Recherche en Cancérologie de Montpellier - IRCM
Langue: English
Type de ressource: Journal article
Champs locaux: hal-02983257