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. * *

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

“…High mitochondrial ETC or OXPHOS activities were repeatedly linked to Venetoclax-or chemotherapy-resistance in AML (13)(14)(15)17) or other cancers (18).…”

“…Mitochondrial dysfunctions can induce the integrated stress response and ROS production, important features of normal or AML stem cells (12). Conversely, mitochondrial fitness and high OXPHOS metabolism have been implicated in resistance to BCL2 inhibitors or conventional chemotherapy (13)(14)(15)(16)(17)(18). Accordingly, inhibitors of mitochondrial respiration were proposed to constitute a novel type of Research.…”

Clinical Implications of Inflammation in Acute Myeloid Leukemia

“…Chemoresistance is also mediated by interactions between AML cells and their microenvironment ( 85 – 87 ). It has been recently demonstrated that an inflammatory and immune interferon-γ signature is associated with chemoresistance ( 88 ).…”

In vivo metabolomic study uncovers distinct metabolic phenotypes of host tissues and predicts oxidative state of acute myeloid leukemia

“…These three metabolites are mainly involved in ROS management through glutathione biosynthesis, folate cycle and transulfuration pathway. It is known that AraC leads to an increase in ROS content in vivo, through enhanced OxPHOS status 4,42 . An increase in these three metabolites in most organs support an adaptation of murine niches to this oxidative stress.…”

“…Most of these metabolites are markedly impactful in our metabolic signature from human patient plasma. The OxPHOS status is described as critical to many drug resistances in AML 4,11,42 . Accordingly, plasma is a tissue of interest for biomarker of the oxidative status of patient blasts to improve management of AML patients.…”