Birsen, R. | bioRxiv Science

bioRxiv2023

Ferritinophagy is a Druggable Vulnerability of Quiescent Leukemic Stem Cells

Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Leukemic stem cells (LSCs) contributes to therapeutic failure, post-therapy relapse and adverse outcome. Here, we investigated the role of quiescence and its associated molecular mechanisms in AML pathogenesis and LSCs functions, and identified potential vulnerabilities for therapeutic intervention. We found that LSC-enriched quiescent cell population exhibited a distinct gene set of prognostic significance in AML patients. Furthermore, this quiescent cells subset displayed heightened autophagic activity with a reliance on ferritinophagy, a selective form of autophagy mediated by Nuclear Receptor Coactivator 4 (NCOA4) regulating iron bioavailability. Inhibition of NCOA4 genetically or chemically showed potent anti-leukemic effects, particularly targeting the LSC compartment. These findings uncover that ferritinophagy inhibition may represent a promising therapeutic strategy for patients with AML. One Sentence SummaryTargeting quiescent leukemic stem cells via NCOA4-dependent ferritinophagy inhibition may improve therapeutic outcomes in acute myeloid leukemia.

cancer biology↗

bioRxiv2022

C/EBPα confers dependence to fatty acid anabolic pathways and vulnerability to lipid oxidative stress in FLT3-mutant leukemia

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.

cancer biology↗