C/EBPalpha Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress-Induced Ferroptosis in FLT3-Mutant Leukemia
Details
Publication Year 2023-07-07,Volume 13,Issue #7,Page 1720-1747
Journal Title
Cancer Discovery
Publication Type
Research article
Abstract
Although transcription factor CCAAT-enhancer binding protein alpha (C/EBPalpha) 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/EBPalpha and Fms-like tyrosine kinase 3 (FLT3) that increased lipid anabolism in vivo and in patients with FLT3-mutant acute myeloid leukemia (AML). Mechanistically, C/EBPalpha 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/EBPalpha inactivation decreased monounsaturated FA incorporation to membrane phospholipids through SCD 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 FLT3-mutant AML cells. Altogether, our study reveals a C/EBPalpha function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML to ferroptosis with promising therapeutic application. SIGNIFICANCE: FLT3 mutations are found in 30% of AML cases and are actionable by tyrosine kinase inhibitors. Here, we discovered that C/EBPalpha 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. This article is highlighted in the In This Issue feature, p. 1501.
Publisher
American Association for Cancer Research
Keywords
Humans; CCAAT-Enhancer-Binding Protein-alpha/genetics/metabolism; fms-Like Tyrosine Kinase 3/genetics/metabolism; *Ferroptosis; Fatty Acids; *Leukemia, Myeloid, Acute/drug therapy/genetics/metabolism; Mutation; Oxidative Stress; Protein Kinase Inhibitors/therapeutic use; Cell Line, Tumor
Department(s)
Clinical Haematology
PubMed ID
37012202
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2023-10-24 04:47:22
Last Modified: 2024-07-16 04:38:32

© 2024 The Walter and Eliza Hall Institute of Medical Research. Access to this website is subject to our Privacy Policy and Terms of Use

An error has occurred. This application may no longer respond until reloaded. Reload 🗙