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-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.

RESAMA: A Network for Monitoring Health and Husbandry Practices in Aquatic Research Facilities.

Health monitoring is a crucial aspect of the management of any research animal house. RESAMA is a network strong of 60 academic and private partners acting in France since the end of 2012. The network aims to increase awareness of animal caretakers and researchers on health management issues in facilities holding aquatic model species (zebrafish, Xenopus, medaka, Mexican tetra). To do so, each partner research facility will be visited at least once. The visiting team is composed at least of one veterinarian and one zootechnician specialized in aquatic species. The visit results in a health-monitoring assessment of the facility, which includes a sampling for histo-pathological, bacteriological, and molecular pathogen detection. During the visit, rearing practices are also reviewed through an interview of animal caretakers. However, the present report essentially focuses on the health-monitoring aspect. The ultimate goal of the project is to provide a network-wide picture of health issues in aquatic facilities. Performed in parallel, the rearing practice assessment will ultimately help to establish rational relationship between handling practices and animal health in aquatic facilities. The study is still in progress. Here, we describe the results to be drawn from an analysis of the 23 facilities that had been visited so far. We sampled 720 fish and 127 amphibians and performed a little less than 1400 individual tests.