FASN inactivation-induced progranulin (GRN) expression promotes lysosome-dependent cell death to suppress leukemogenesis - PubMed
5 days ago
- #lysosome
- #leukemia
- #FASN
- FASN inactivation induces progranulin (GRN) expression, promoting lysosome-dependent cell death to suppress leukemogenesis.
- FASN is essential for leukemogenesis; its genetic ablation impairs leukemic cell growth, survival, and clonogenicity without significantly affecting normal hematopoiesis.
- A platensimycin derivative, MS-C19, is identified as a potent FASN inhibitor, suppressing growth and clonogenicity in clinical AML samples.
- FASN inhibition activates lysosomal and inflammatory gene programs, leading to lysosomal membrane permeabilization and associated cell death, but not lysosome biogenesis.
- GRN is transcribed by TFEB upon FASN inhibition, and its depletion reverses the anti-leukemic effects of FASN loss.
- FASN is established as a therapeutic target, with MS-C19 proposed as a pharmacological inhibitor for leukemia treatment.