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 SyrykhCamille 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*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

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 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. SIGNIFICANCE: Extracellular ATP and CD39–P2RY13–cAMP–OxPHOS axis are key regulators of cyta-rabine resistance, offering a new promising therapeutic strategy in AML.

Original languageEnglish
Pages (from-to)1544-1565
Number of pages22
JournalCancer Discovery
Volume10
Issue number10
DOIs
Publication statusPublished - 2020

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