Restored biosynthetic pathways induced by MSCs serve as rescue mechanism in leukemia cells after L-asparaginase therapy

Abstract

L-asparaginase (ASNase), the drug included on the World Health Organization's List of EssentialMedicines, is irreplaceable in the front-line treatment of childhood acute lymphoblastic leukemia(ALL)1 . However, the relapse of ALL is often associated with resistance to ASNase and itsmechanisms are not fully understood. The cytotoxic effect of ASNase relies on depleting exogenousasparagine (Asn) and glutamine (Gln), inducing apoptosis in leukemic cells because of their reducedcapability of Asn synthesis. Our previous in vitro data demonstrated that ASNase triggers metabolicreprogramming of leukemic cells which impedes the anti-leukemic effect. Metabolic processes ofleukemic cells have been shown to be altered by the environment of the bone marrow (BM) whichmay contribute to chemoresistance. Herein, we investigated the impact of BM attributes oncellular metabolic processes of leukemic cells in order to demonstrate the more complex picture ofASNase-driven metabolic rewiring and its role in the mechanism of resistance.