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Functional Role of Fatty Acid Synthase for Signal Transduction in Core-Binding Factor Acute Myeloid Leukemia with an Activating c-Kit Mutation

Affiliation
Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;(R.Z.);(M.J.)
Zhuang, Ruimeng;
ORCID
0000-0001-9183-0381
Affiliation
Section Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;(B.S.);(H.S.)
Siebels, Bente;
Affiliation
Department of Radiobiology & Radiation Oncology, UCCH Kinomics Core Facility, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;(K.H.);(M.K.)
Hoffer, Konstantin;
Affiliation
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
Worthmann, Anna;
Affiliation
Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
Horn, Stefan;
Affiliation
Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 Lübeck, Germany;(N.C.C.v.B.);(C.K.);(N.G.);(S.P.G.)
von Bubnoff, Nikolas Christian Cornelius;
ORCID
0000-0003-4655-6269
Affiliation
Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 Lübeck, Germany;(N.C.C.v.B.);(C.K.);(N.G.);(S.P.G.)
Khandanpour, Cyrus;
ORCID
0000-0003-0566-4554
Affiliation
Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 Lübeck, Germany;(N.C.C.v.B.);(C.K.);(N.G.);(S.P.G.)
Gebauer, Niklas;
Affiliation
Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 Lübeck, Germany;(N.C.C.v.B.);(C.K.);(N.G.);(S.P.G.)
Gorantla, Sivahari Prasad;
Affiliation
Section Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;(B.S.);(H.S.)
Voss, Hanna;
ORCID
0000-0002-9358-7036
Affiliation
Section Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;(B.S.);(H.S.)
Schlüter, Hartmut;
Affiliation
Department of Radiobiology & Radiation Oncology, UCCH Kinomics Core Facility, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;(K.H.);(M.K.)
Kriegs, Malte;
ORCID
0000-0003-0275-8803
Affiliation
Hubertus Wald Tumorzentrum, Department of Oncology–Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, 20251 Hamburg, Germany;(W.F.);(C.B.)
Fiedler, Walter;
ORCID
0000-0001-6071-7810
Affiliation
Hubertus Wald Tumorzentrum, Department of Oncology–Hematology, Bone Marrow Transplantation and Pneumology, University Cancer Center, 20251 Hamburg, Germany;(W.F.);(C.B.)
Bokemeyer, Carsten;
ORCID
0000-0003-2176-6526
Affiliation
Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;(R.Z.);(M.J.)
Jücker, Manfred;
Affiliation
Clinic for Hematology and Oncology, University Hospital Schleswig-Holstein Campus, 23562 Lübeck, Germany;(N.C.C.v.B.);(C.K.);(N.G.);(S.P.G.)
Kebenko, Maxim

Background/Objectives : Acute myeloid leukemia (AML) is a rare hematological malignancy with a poor prognosis. Activating c-Kit (CD117) mutations occur in 5% of de novo AML and 30% of core-binding factor (CBF) AML, leading to worse clinical outcomes. Posttranslational modifications, particularly with myristic and palmitic acid, are crucial for various cellular processes, including membrane organization, signal transduction, and apoptosis regulation. However, most research has focused on solid tumors, with limited understanding of these mechanisms in AML. Fatty acid synthase (FASN), a key palmitoyl-acyltransferase, regulates the subcellular localization, trafficking, and degradation of target proteins, such as H-Ras, N-Ras, and FLT3-ITDmut receptors in AML. Methods : In this study, we investigated the role of FASN in two c-Kit-N822K-mutated AML cell lines using FASN knockdown via shRNA and the FASN inhibitor TVB-3166. Functional implications, including cell proliferation, were assessed through Western blotting, mass spectrometry, and PamGene. Results : FASN inhibition led to an increased phosphorylation of c-Kit (p-c-Kit), Lyn kinase (pLyn), MAP kinase (pMAPK), and S6 kinase (pS6). Furthermore, we observed sustained high expression of Gli1 in Kasumi1 cells following FASN inhibition, which is well known to be mediated by the upregulation of pS6. Conclusions : The combination of TVB-3166 and the Gli inhibitor GANT61 resulted in a significant reduction in the survival of Kasumi1 cells.

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Editor:
Zou, Ying S.; Yenwongfai, Leonard N.
Published in:
Biomedicines  
Vol. 13, No. 3 (03.03.2025)
Volume:
13
No.:
3
Date Issued:
03.03.2025
DOI:
10.3390/biomedicines13030619
Language:
English
Type of Resource:
Text
Keywords:
fatty acid synthase; palmitoylation; TVB-3166; AML; c-Kit mutation; PI3K; Akt; mTOR; S6 kinase; Lyn; Gli1; hedgehog signaling
DDC:
610 Medizin und Gesundheit

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