Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cancer Discovery Année : 2020

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

Floriant Bellvert
Jean-Charles Portais
Tony Kaoma

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.

Domaines

Cancer

Dates et versions

hal-02983257 , version 1 (29-10-2020)

Identifiants

Citer

Nesrine Aroua, Emeline Boet, Margherita Ghisi, Marie-Laure Nicolau-Travers, Estelle Saland, et al.. Extracellular ATP and CD39 Activate cAMP-Mediated Mitochondrial Stress Response to Promote Cytarabine Resistance in Acute Myeloid Leukemia. Cancer Discovery, 2020, 10 (10), pp.1544-1565. ⟨10.1158/2159-8290.CD-19-1008⟩. ⟨hal-02983257⟩
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