{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:28:00Z","timestamp":1787725680663,"version":"build-2784847793"},"reference-count":28,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T00:00:00Z","timestamp":1749859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["INST 337\/15-1"],"award-info":[{"award-number":["INST 337\/15-1"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["INST 337\/16-1"],"award-info":[{"award-number":["INST 337\/16-1"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["INST 152\/837-1"],"award-info":[{"award-number":["INST 152\/837-1"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["INST 152\/947-1 FUGG"],"award-info":[{"award-number":["INST 152\/947-1 FUGG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog\u2013Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog\u2013Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells.<\/jats:p>","DOI":"10.3390\/ijms26125721","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T09:51:22Z","timestamp":1750067482000},"page":"5721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Downregulation of S6 Kinase and Hedgehog\u2013Gli1 by Inhibition of Fatty Acid Synthase in AML with FLT3-ITD Mutation"],"prefix":"10.3390","volume":"26","author":[{"given":"Maxim","family":"Kebenko","sequence":"first","affiliation":[{"name":"Hubertus Wald Tumorzentrum, Department of Oncology\u2013Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, 20246 Hamburg, Germany"},{"name":"Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruimeng","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7446-3075","authenticated-orcid":false,"given":"Konstantin","family":"Hoffer","sequence":"additional","affiliation":[{"name":"Department of Radiobiology & Radiation Oncology, UCCH Kinomics Core Facility, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Worthmann","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Horn","sequence":"additional","affiliation":[{"name":"Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Kriegs","sequence":"additional","affiliation":[{"name":"Department of Radiobiology & Radiation Oncology, UCCH Kinomics Core Facility, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Vorwerk","sequence":"additional","affiliation":[{"name":"Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9593-8947","authenticated-orcid":false,"given":"Nikolas","family":"von Bubnoff","sequence":"additional","affiliation":[{"name":"Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4655-6269","authenticated-orcid":false,"given":"Cyrus","family":"Khandanpour","sequence":"additional","affiliation":[{"name":"Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0566-4554","authenticated-orcid":false,"given":"Niklas","family":"Gebauer","sequence":"additional","affiliation":[{"name":"Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivahari Prasad","family":"Gorantla","sequence":"additional","affiliation":[{"name":"Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0275-8803","authenticated-orcid":false,"given":"Walter","family":"Fiedler","sequence":"additional","affiliation":[{"name":"Hubertus Wald Tumorzentrum, Department of Oncology\u2013Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6071-7810","authenticated-orcid":false,"given":"Carsten","family":"Bokemeyer","sequence":"additional","affiliation":[{"name":"Hubertus Wald Tumorzentrum, Department of Oncology\u2013Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-6526","authenticated-orcid":false,"given":"Manfred","family":"J\u00fccker","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1056\/NEJMoa1516192","article-title":"Genomic Classification and Prognosis in Acute Myeloid Leukemia","volume":"374","author":"Papaemmanuil","year":"2016","journal-title":"N. 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