{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:28:31Z","timestamp":1789730911777,"version":"4.0.1"},"reference-count":34,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":48,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NCI","award":["CA244625"],"award-info":[{"award-number":["CA244625"]}]},{"name":"NIH\/NCI","award":["CA244625"],"award-info":[{"award-number":["CA244625"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,22]]},"abstract":"<jats:p>\n                    Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B and T cell lineages (B-ALL and T-ALL). Current therapy exploits ALL cells\u2019 low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and the ASNS inhibitor ASX-173. Using a\n                    <jats:italic>\n                      Kras\n                      <jats:sup>G12D<\/jats:sup>\n                    <\/jats:italic>\n                    -driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of\n                    <jats:italic>Gcn2<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS\n                    <jats:sup>hi<\/jats:sup>\n                    leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high levels of ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.203777","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T16:00:18Z","timestamp":1780588818000},"source":"Crossref","is-referenced-by-count":1,"title":["Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy"],"prefix":"10.1172","volume":"11","author":[{"given":"Rodney","family":"Claude","sequence":"first","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research,"},{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, and"},{"name":"Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sankalp","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research,"},{"name":"Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk A.","family":"Staschke","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology, and Pharmacology, and"},{"name":"Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Mellado-Fritz","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research & Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxiong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghua","family":"Zhong","sequence":"additional","affiliation":[{"name":"Herman B. Wells Center for Pediatric Research,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harish","family":"Kothandaraman","sequence":"additional","affiliation":[{"name":"Purdue University Institute for Cancer Research, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1819-7070","authenticated-orcid":true,"given":"Nadia A.","family":"Lanman","sequence":"additional","affiliation":[{"name":"Purdue University Institute for Cancer Research, and"},{"name":"Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utpal","family":"Dav\u00e9","sequence":"additional","affiliation":[{"name":"Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Batra","sequence":"additional","affiliation":[{"name":"Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiehao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Phoenix, Arizona, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-0925","authenticated-orcid":true,"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuben","family":"Kapur","sequence":"additional","affiliation":[{"name":"Herman B. 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