Article ; Online: C/EBPα Confers Dependence to Fatty Acid Anabolic Pathways and Vulnerability to Lipid Oxidative Stress-Induced Ferroptosis in FLT3-Mutant Leukemia.
2023 Volume 13, Issue 7, Page(s) 1720–1747
Abstract: 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 ... ...
| Abstract | 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 in vivo and in patients with FLT3-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 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/EBPα 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/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. This article is highlighted in the In This Issue feature, p. 1501. |
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| MeSH term(s) | Humans ; CCAAT-Enhancer-Binding Protein-alpha/genetics ; CCAAT-Enhancer-Binding Protein-alpha/metabolism ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism ; Ferroptosis ; Fatty Acids ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mutation ; Oxidative Stress ; Protein Kinase Inhibitors/therapeutic use ; Cell Line, Tumor | |||||
| Chemical Substances | CCAAT-Enhancer-Binding Protein-alpha ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; Fatty Acids ; Protein Kinase Inhibitors ; FLT3 protein, human (EC 2.7.10.1) | |||||
| Language | English | |||||
| Publishing date | 2023-04-03 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2625242-9 | |||||
| ISSN | 2159-8290 ; 2159-8274 | |||||
| ISSN (online) | 2159-8290 | |||||
| ISSN | 2159-8274 | |||||
| DOI | 10.1158/2159-8290.CD-22-0411 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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