l-asparaginase (ASNase), a key component in the treatment of childhood acute lymphoblastic leukemia (ALL), hydrolyzes plasma asparagine and glutamine and thereby disturbs metabolic homeostasis of leukemic cells. The efficacy of such therapeutic strategy will depend on the capacity of cancer cells to adapt to the metabolic challenge, which could relate to the activation of compensatory metabolic routes. Therefore, we studied the impact of ASNase on the main metabolic pathways in leukemic cells. Treating leukemic cells with ASNase increased fatty-acid oxidation (FAO) and cell respiration and inhibited glycolysis. FAO, together with the decrease in protein translation and pyrimidine synthesis, was positively regulated through inhibition of the RagB-mTORC1 pathway, whereas the effect on glycolysis was RagB-mTORC1 independent. As FAO has been suggested to have a pro-survival function in leukemic cells, we tested its contribution to cell survival following ASNase treatment. Pharmacological inhibition of FAO significantly increased the sensitivity of ALL cells to ASNase. Moreover, constitutive activation of the mammalian target of rapamycin pathway increased apoptosis in leukemic cells treated with ASNase, but did not increase FAO. Our study uncovers a novel therapeutic option based on the combination of ASNase and FAO inhibitors.

CIC bioGUNE Technology Park of Bizkaia Derio Spain

CLIP Childhood Leukaemia Investigation Prague Department of Pediatric Hematology Oncology Charles University Prague Prague Czech Republic

Department of Biochemistry and Molecular biology University of the Basque Country Leioa Spain

Department of Biochemistry Charles University Prague Czech Republic

Department of Bioenergetics Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Equipe 11 labellisée par la Ligue Nationale Contre le Cancer; INSERM U1138; Centre de Recherche des Cordeliers Paris France

Ikerbasque Basque Foundation for Science Bilbao Spain

Laboratory of Molecular Immunology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Structural Biology and Cell Signaling Institute of Microbiology Academy of Sciences of the Czech Republic Prague Czech Republic

Metabolomics and Molecular Cell Biology Platforms; Gustave Roussy Villejuif France

Pôle de Biologie; Hôpital Européen Georges Pompidou; AP HP Paris France

Université Paris Descartes; Sorbonne Paris Cité Paris France

University Hospital Motol Prague Czech Republic

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