{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:36:08Z","timestamp":1791408968590,"version":"4.3.3"},"reference-count":39,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T00:00:00Z","timestamp":1444953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007451","name":"Cell Science Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007451","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008373","name":"Takeda Pharmaceutical Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004095","name":"Kyowa Hakko Kirin","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004095","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:p>L\u2010asparaginase (L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase) is an important branch of chemotherapy for acute lymphoblastic leukemia (<jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>) and some types of non\u2010Hodgkin's lymphoma, including natural killer (<jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>)\u2010cell 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\u2010tumor activity in therapeutic doses is unclear in <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content> and malignant lymphoma. Here we demonstrate that L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase exerts cytotoxicity through targeting the Gln addiction phenotype in lymphoid cell lines. A clinically attainable intermediate dose of L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase induced massive apoptosis in <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content> Jurkat and mantle cell lymphoma Jeko cell lines, while a low dose of L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase effectively killed <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>\u2010cell 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\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase. L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase treatment and Gln deprivation dramatically disrupted the refilling of the tricarboxylic acid (<jats:styled-content style=\"fixed-case\">TCA<\/jats:styled-content>) cycle by intracellular glutamate (Glu) and disturbed the mitochondrial integrity, which were alleviated by various anaplerotic <jats:styled-content style=\"fixed-case\">TCA<\/jats:styled-content> cycle intermediates, suggesting a direct contribution of glutaminase activity of L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase. The action of L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase differs between Jurkat cells and <jats:styled-content style=\"fixed-case\">NK<\/jats:styled-content>\u2010cell lymphoma cells, according to their dependence on Gln and Asn. Furthermore, we observed that high expression of glutaminase <jats:styled-content style=\"fixed-case\">GLS<\/jats:styled-content>1 is associated with increased sensivity to L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase in pediatric B lineage <jats:styled-content style=\"fixed-case\">ALL<\/jats:styled-content>. Our results redefine L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase as a therapeutic agent targeting Gln addiction in certain lymphoid cells and offer an additional basis for predicting L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase sensitivity and engineering selective L\u2010<jats:styled-content style=\"fixed-case\">ASN<\/jats:styled-content>ase derivatives for leukemia and lymphoma.<\/jats:p>","DOI":"10.1111\/cas.12807","type":"journal-article","created":{"date-parts":[[2015,9,2]],"date-time":"2015-09-02T15:52:01Z","timestamp":1441209121000},"page":"1534-1543","source":"Crossref","is-referenced-by-count":32,"title":["A clinically attainable dose of L\u2010asparaginase targets glutamine addiction in lymphoid cell lines"],"prefix":"10.1111","volume":"106","author":[{"given":"Koichi","family":"Sugimoto","sequence":"first","affiliation":[{"name":"Division of Hematology Department of Internal Medicine Juntendo University School of Medicine Tokyo Japan"},{"name":"Department of Hematology and Oncology JR Tokyo General Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi I.","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology Graduate School of Medicine The University of Tokyo Tokyo Japan"},{"name":"David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Fujimura","sequence":"additional","affiliation":[{"name":"Laboratory of Proteomics and BioMolecular Science Biomedical Research Center Juntendo University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asami","family":"Ono","sequence":"additional","affiliation":[{"name":"Division of Hematology Department of Internal Medicine Juntendo University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Kaga","sequence":"additional","affiliation":[{"name":"Laboratory of Proteomics and BioMolecular Science Biomedical Research Center Juntendo University School of Medicine Tokyo 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