Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct;10(10):1544-1565.
doi: 10.1158/2159-8290.CD-19-1008. Epub 2020 Jul 8.

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

Nesrine Aroua #  1   2 , Emeline Boet #  1   2 , Margherita Ghisi #  1   2 , Marie-Laure Nicolau-Travers  1   2   3 , Estelle Saland  1   2 , Ryan Gwilliam  1   2 , Fabienne de Toni  1   2 , Mohsen Hosseini  1   2 , Pierre-Luc Mouchel  1   2   3 , Thomas Farge  1   2 , Claudie Bosc  1   2 , Lucille Stuani  1   2 , Marie Sabatier  1   2 , Fetta Mazed  4   5 , Clément Larrue  1   2 , Latifa Jarrou  1   2 , Sarah Gandarillas  6 , Massimiliano Bardotti  6 , Muriel Picard  2   7 , Charlotte Syrykh  1   2   8 , Camille Laurent  1   2   8 , Mathilde Gotanègre  1   2 , Nathalie Bonnefoy  9 , Floriant Bellvert  10 , Jean-Charles Portais  10 , Nathalie Nicot  11 , Francisco Azuaje  12 , Tony Kaoma  12 , Carine Joffre  1   2 , Jérome Tamburini  4   5 , Christian Récher  1   2   3 , François Vergez  1   2   3 , Jean-Emmanuel Sarry  13   2
Affiliations

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

Nesrine Aroua et al. Cancer Discov. 2020 Oct.

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 cytarabine resistance, offering a new promising therapeutic strategy in AML.This article is highlighted in the In This Issue feature, p. 1426.

PubMed Disclaimer

References

    1. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood. 2005;106:1154–63.
    1. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29:487–94.
    1. Vergez F, Green AS, Tamburini J, Sarry J-E, Gaillard B, Cornillet-Lefebvre P, et al. High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study. Haematologica. 2011;96:1792–8.
    1. van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S, et al. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res. 2005;11:6520–7.
    1. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25:1315–21.

Publication types