{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T02:46:48Z","timestamp":1773370008669,"version":"3.50.1"},"posted":{"date-parts":[[2025,11,24]]},"group-title":"Cancer Biology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"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"}]},{"name":"National Cancer Institute","award":["P30CA134274"],"award-info":[{"award-number":["P30CA134274"]}]},{"name":"National Cancer Institute","award":["P30CA006973"],"award-info":[{"award-number":["P30CA006973"]}]},{"name":"National Cancer Institute","award":["R01CA277031"],"award-info":[{"award-number":["R01CA277031"]}]},{"name":"National Cancer Institute","award":["U01CA271412"],"award-info":[{"award-number":["U01CA271412"]}]},{"name":"National Cancer Institute","award":["U54CA224019"],"award-info":[{"award-number":["U54CA224019"]}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["MRSG-17-040-01-LIB"],"award-info":[{"award-number":["MRSG-17-040-01-LIB"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  FLT3 inhibitor efficacy in AML with FLT3-ITD is short-lived, frequently due to new mutations, most commonly in\n                  <jats:italic>NRAS<\/jats:italic>\n                  . Sphingosine kinase 1 (SPHK1), which phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), is upregulated and localized to the plasma membrane in\n                  <jats:italic>RAS<\/jats:italic>\n                  -mutated cells. We studied S1P and FLT3 co-targeting to overcome FLT3 inhibitor resistance in\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutated FLT3-ITD AML cells.\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutated FLT3-ITD AML cell lines and patient blasts were treated with FLT3 inhibitors and\/or S1P receptor (S1PR) modulators. FLT3 inhibitor sensitivity was assessed by immunoblotting, cytotoxicity and apoptosis assays. Co-treatment was also assessed\n                  <jats:italic>in vivo<\/jats:italic>\n                  in an orthotopic mouse model. Downstream RAS and SPHK1 effectors were measured by immunoblotting and qRT-PCR. The S1PR modulators fingolimod (FTY720) and mocravimod (KRP-203) resensitized FLT3-ITD-expressing MOLM-14 and MV4-11 human AML cells with G12D, G12S, Q61K or Q61H, but not G12C, and patient blasts with G13D or G13V\n                  <jats:italic>NRAS<\/jats:italic>\n                  mutations to FLT3 inhibitors. Moreover, FTY720 co-treatment resensitized G12D\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutated M14(R)701 cells to gilteritinib\n                  <jats:italic>in vivo.<\/jats:italic>\n                  Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy of these combinations.\n                <\/jats:p>","DOI":"10.1101\/2025.11.21.689510","type":"posted-content","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T21:45:18Z","timestamp":1764020718000},"source":"Crossref","is-referenced-by-count":1,"title":["Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with\n                  <i>NRAS<\/i>\n                  mutations to FLT3 inhibitors"],"prefix":"10.64898","author":[{"given":"Aditi","family":"Chatterjee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moaath K.","family":"Mustafa Ali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Bailey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuchen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald","family":"Small","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine 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