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• W4382022994 abstract "<div>Abstract<p>Although transcription factor CCAAT-enhancer binding protein α (C/EBPα) is critical for normal and leukemic differentiation, its role in cell and metabolic homeostasis is largely unknown in cancer. Here, multiomics analyses uncovered a coordinated activation of C/EBPα and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism <i>in vivo</i> and in patients with <i>FLT3</i>-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPα regulated the fatty acid synthase (FASN)–stearoyl-CoA desaturase (SCD) axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBPα inactivation decreased monounsaturated FA incorporation to membrane phospholipids through <i>SCD</i> downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress that was exploited by combining FLT3 and glutathione peroxidase 4 inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of <i>FLT3</i>-mutant AML cells. Altogether, our study reveals a C/EBPα function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of <i>FLT3</i>-mutant AML to ferroptosis with promising therapeutic application.</p>Significance:<p><i>FLT3</i> mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPα regulates FA biosynthesis and protection from lipid redox stress downstream mutant-FLT3 signaling, which confers a vulnerability to ferroptosis upon FLT3 inhibition with therapeutic potential in AML.</p><p><i><a href=https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-7-ITI target=_blank>This article is highlighted in the In This Issue feature, p. 1501</a></i></p></div>" @default.
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• W4382022994 date "2023-07-07" @default.
• W4382022994 modified "2023-10-15" @default.
• W4382022994 title "Data from C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress–Induced Ferroptosis in <i>FLT3</i>-Mutant Leukemia" @default.
• W4382022994 doi "https://doi.org/10.1158/2159-8290.c.6713553" @default.
• W4382022994 hasPublicationYear "2023" @default.
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