{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:12:50Z","timestamp":1779207170092,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,6]]},"group-title":"Cancer Biology","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000738","name":"United States Department of Veterans Affairs","doi-asserted-by":"crossref","award":["BX005120"],"award-info":[{"award-number":["BX005120"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["IRG-24-1290479-19"],"award-info":[{"award-number":["IRG-24-1290479-19"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["P30CA134274"],"award-info":[{"award-number":["P30CA134274"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  FLT3 inhibitors have improved outcomes in acute myeloid leukemia (AML) with\n                  <jats:italic>FMS<\/jats:italic>\n                  -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), but responses are not durable. Notably, FLT3 inhibitors clear blasts from the blood, but not the bone marrow, a hypoxic niche. We investigated effects of hypoxia and the key nutrient glutamine on FLT3 inhibitor response. FLT3-ITD AML cell lines and patient blasts were cultured with FLT3 inhibitors under normoxia (21%) or hypoxia (&lt;1% O\n                  <jats:sub>2<\/jats:sub>\n                  ) with or without glutamine or the glutaminase inhibitor telaglenastat (CB-839). Cytotoxicity was measured in WST-1 assays and drug combination effects by Chou-Talalay analysis. Protein expression was measured by immunoblotting, turnover and proteasomal degradation by cycloheximide chase with and without MG-132, and mRNA expression by RT-qPCR. Effect of the ubiquitin ligase c-CBL was tested by siRNA knockdown. FLT3 inhibitor IC\n                  <jats:sub>50<\/jats:sub>\n                  s were 3-5-fold higher in hypoxia than normoxia, associated with FLT3-ITD and p-STAT5 downregulation and accelerated FLT3-ITD proteasomal degradation (half-life, 1.0 vs. 2.5 hours). c-CBL expression increased in hypoxia, and c-CBL knockdown restored FLT3-ITD expression and FLT3 inhibitor sensitivity. Glutamine deprivation or telaglenastat treatment abrogated c-CBL upregulation in hypoxia and preserved FLT3-ITD and p-STAT5 expression and FLT3 inhibitor sensitivity. Telaglenastat synergized with FLT3 inhibitors in hypoxia, supporting clinical testing.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"722336v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.02.722336","type":"posted-content","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T22:45:14Z","timestamp":1778107514000},"source":"Crossref","is-referenced-by-count":0,"title":["Glutamine-Dependent Downregulation of FLT3-ITD is a Mechanism of FLT3 Inhibitor Resistance in FLT3-ITD AML in Hypoxia"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5911-6997","authenticated-orcid":false,"given":"Giovannino","family":"Silvestri","sequence":"first","affiliation":[{"name":"University of Maryland Greenebaum Comprehensive Cancer Center,"},{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0595-3866","authenticated-orcid":false,"given":"Aditi","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"University of Maryland Greenebaum Comprehensive Cancer Center,"},{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blair P.","family":"Rendina","sequence":"additional","affiliation":[{"name":"Department of Pathology"},{"name":"Neurosurgery University of Maryland School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4561-4631","authenticated-orcid":false,"given":"Eli E.","family":"Bar","sequence":"additional","affiliation":[{"name":"University of Maryland Greenebaum Comprehensive Cancer Center,"},{"name":"Department of Pathology"},{"name":"Neurosurgery University of Maryland School of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-1348","authenticated-orcid":false,"given":"Maria R.","family":"Baer","sequence":"additional","affiliation":[{"name":"University of Maryland Greenebaum Comprehensive Cancer Center,"},{"name":"Department of Medicine"},{"name":"Veterans Affairs Medical Center, Baltimore, MD, 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