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

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 (AraC)-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 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 cells in vitro and in vivo. Together, these results reveal CD39 as a new prognostic marker and a promising therapeutic target to improve chemotherapy response in AML. SIGNIFICANCE: Extracellular ATP and CD39-cAMP-OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML.

Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma

“…We next investigated the function of CD39 in HCC. Recent studies have observed a high level of CD39 in tumor-infiltrating immune cells from many tumors [ 12 , 24 , 25 ]. Some tumors including kidney, lung, testicular, and thyroid tumor cells, but not HCC, express a high level of CD39 [ 26 ].…”

Identification of P2RY13 as an immune-related prognostic biomarker in lung adenocarcinoma: A public database-based retrospective study

“…The present study found that the expression level of P2RY13 in LUAD tissues was downregulated. However, previous studies reported that P2RY13 expression in acute myeloid leukemia was increased, and regulated cyclic adenosine monophosphate-mediated cytarabine resistance ( Aroua et al, 2020 ; Maiga et al, 2016 ). To date, there is no basic research on the role of P2RY13 in LUAD, nor studies on the role of P2RY13 on the TME or immune reactions in LUAD.…”

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

“…Overall, our studies suggested the multifunctional roles of ATP as an energy supplier facilitating drug efflux and a signaling transducer activating signaling pathways related to cell survival and resistance, drug efflux and tumor migration/invasion. eATP can also contribute to cancer drug resistance as an extracellular messenger through P2 purinergic signaling, which is composed of nucleotides/nucleosides (mainly ATP and adenosine) acting as signaling ligands with their corresponding membrane receptors and modulating diverse signaling pathways [206] . There are two P2 receptor families: P2X receptors which are ATP-gated ion channels and P2Y receptors which are mainly activated by ATP or ADP.…”

“…There are two P2 receptor families: P2X receptors which are ATP-gated ion channels and P2Y receptors which are mainly activated by ATP or ADP. P2X and P2Y family members emerge as players in resistance to chemotherapies [ 207 , 208 ] . Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, or CD39) eATPase activity, which converts eATP to AMP, coordinately activated mitochondrial stress response via the downstream P2RY13/cAMP/PKA axis and promoted cytarabine resistance by enhancing mitochondrial OXPHOS activity in acute myeloid leukemia (AML).…”

“…Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, or CD39) eATPase activity, which converts eATP to AMP, coordinately activated mitochondrial stress response via the downstream P2RY13/cAMP/PKA axis and promoted cytarabine resistance by enhancing mitochondrial OXPHOS activity in acute myeloid leukemia (AML). With such evidence, eATP was proposed as a key factor in chemoresistance of AML and CD39 as a new marker associated with a poor response to chemotherapy [ 207 ] . In the extracellular compartment, tumor cells can induce platelet activation and aggregation.…”