Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia

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 (AraC)-resistant leukemic cells from both AML cell lines and patient samplesin vivoandin vitro. CD39 cell surface expression and activity is increased in AML patients upon chemotherapy compared to diagnosis and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes AraC resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated response. Finally, genetic and pharmacological inhibition of CD39 eATPase activity blocks the mitochondrial reprogramming triggered by AraC treatment and markedly enhances its cytotoxicity in AML cellsin vitroandin vivo. Together, these results reveal CD39 as a new prognostic marker and a promising therapeutic target to improve chemotherapy response in AML.SIGNIFICANCEExtracellular ATP and CD39-cAMP-OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML.