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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

ABSTRACT: Acute myeloid leukemia (AML) is a rare hematological malignancy with a poor prog-nosis. 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 regu-lation. However, most research has focused on solid tumors, with limited understanding of these mechanisms in AML. Fatty acid synthase (FASN), a key palmito-yl-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 im-plications, including cell proliferation, were assessed through Western blotting, mass spectrometry, and PamGene. Results: FASN inhibition led to an increased phosphory-lation 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Bente Siebels

LAB HEAD: Dr. Maxim

PROVIDER: PXD048252 | Pride | 2025-03-05

REPOSITORIES: Pride

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	220509_BS_Kebenko_7a.raw	Raw
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	220509_BS_Kebenko_7c.raw	Raw
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