Abstract

While transcription factor C/AAT-enhancer binding protein (C/EBP) is critical for normal and leukemic differentiation, its role on cell and metabolic homeostasis is largely unknown in cancer. Here, multi-omics analyses uncovered a coordinated activation of C/EBP 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/EBP regulated FASN-SCD axis to promote fatty acid (FA) biosynthesis and desaturation. We further demonstrated that FLT3 or C/EBP inactivation decreased mono-unsaturated FAs incorporation to membrane phospholipids through SCD downregulation. Consequently, SCD inhibition enhanced susceptibility to lipid redox stress. Moreover, this C/EBP-dependent adaptation of FA homeostasis was exploited by combining FLT3 and glutathione peroxidase 4 (GPX4) inhibition to trigger lipid oxidative stress, enhancing ferroptotic death of FLT3-mutant AML cells. Altogether, our study reveals a C/EBP function in lipid homeostasis and adaptation to redox stress, and a previously unreported vulnerability of FLT3-mutant AML with promising therapeutic application. SIGNIFICANCEThe transcription factor C/EBP is as a master regulator of normal and leukemic myeloid differentiation. Here, we discovered that C/EBP regulates fatty acid biosynthesis and metabolic adaptation to redox imbalance in leukemic cells. This confers a vulnerability to lipid oxidative stress to FLT3-mutant cells and supports novel therapeutic opportunities for patients.