Su, M.; Lv, Z.; Lu, Y.; Xie, X.; Zou, A.; Liu, H.; Ouyang, J.; Li, Q.; Ma, X.; Yang, Y.; Liu, K.; He, Y.; Xu, S.; Li, J.; Chen, L.; Lu, X.; Yang, J.; Liu, L.; Wu, C.; Zhang, L.; Sheng, Y.; Huang, Y.; Mei, Y.

Cancer cells rely on lipogenesis in addition to exogenous lipid uptake, and fatty acid synthase (FASN) is aberrantly overexpressed in myeloid leukemia. However, the precise role of FASN in leukemogenesis in vivo remains elusive. Here, we demonstrated that FASN is essential for leukemogenesis. Ablation of FASN impeded leukemic cell growth, survival, clonogenicity in vitro, and the leukemic burden in vivo. Conditional knockout of FASN barely affected hematopoiesis but significantly attenuated the leukemic progression of MLL-AF9 transplants. By screening a library of platensimycin derivatives, we identified compound MS-C19 as a potent FASN inhibitor. Pharmacological targeting of FASN by MS-C19 suppressed leukemic cell growth and clonogenicity in clinical AML blasts. Mechanistically, both MS-C19 treatment and FASN deficiency triggered the activation of lysosomal and inflammatory gene expression. Loss of FASN led to lysosomal membrane permeabilization and subsequent lysosome-associated cell death, but not lysosome biogenesis. We further identified that GRN, a lysosomal and neuroinflammatory gene, was potently transcribed by TFEB upon FASN loss. Depletion of GRN significantly reversed the inhibitory effects caused by FASN knockdown. Our work demonstrates that FASN is a therapeutic target for myeloid leukemia, and inactivation of FASN by the lead compound MS-C19 provides an alternative approach for leukemic intervention.