A clinically attainable dose of L‐asparaginase targets glutamine addiction in lymphoid cell lines

L‐asparaginase (L‐ASNase) is an important branch of chemotherapy for acute lymphoblastic leukemia (ALL) and some types of non‐Hodgkin's lymphoma, including natural killer (NK)‐cell lymphoma. Although it mediates hydrolysis of asparagine (Asn) and glutamine (Gln), which are variably required for cancer cell survival, the relative contribution of Asn and Gln depletion to the anti‐tumor activity in therapeutic doses is unclear in ALL and malignant lymphoma. Here we demonstrate that L‐ASNase exerts cytotoxicity through targeting the Gln addiction phenotype in lymphoid cell lines. A clinically attainable intermediate dose of L‐ASNase induced massive apoptosis in ALL Jurkat and mantle cell lymphoma Jeko cell lines, while a low dose of L‐ASNase effectively killed NK‐cell lymphoma cells. In the lymphoid cell lines Jurkat and Jeco, deprivation of Gln but not Asn specifically suppressed cell growth and survival, and phenocopied the action of L‐ASNase. L‐ASNase treatment and Gln deprivation dramatically disrupted the refilling of the tricarboxylic acid (TCA) cycle by intracellular glutamate (Glu) and disturbed the mitochondrial integrity, which were alleviated by various anaplerotic TCA cycle intermediates, suggesting a direct contribution of glutaminase activity of L‐ASNase. The action of L‐ASNase differs between Jurkat cells and NK‐cell lymphoma cells, according to their dependence on Gln and Asn. Furthermore, we observed that high expression of glutaminase GLS1 is associated with increased sensivity to L‐ASNase in pediatric B lineage ALL. Our results redefine L‐ASNase as a therapeutic agent targeting Gln addiction in certain lymphoid cells and offer an additional basis for predicting L‐ASNase sensitivity and engineering selective L‐ASNase derivatives for leukemia and lymphoma.