Fatty Acid Synthase (FASN) Maintains Leukemogenesis By Suppressing Progranulin-Engaged Lysosomal and Inflammatory Signaling

Cancer cells rely on lipogenesis in addition to the exogenous lipid up-taking, in which the lipogenic enzyme fatty acid synthase has aberrant over-expression in various cancers, including myeloid leukemia. However, the precise role of FASN in the leukemogenesis remains elucidative. Here, by genetic manipulation of FASN in vitro and in vivo, we demonstrated that FASN was essential for leukemogenesis. Ablation of FASN either by RNA interference or CRISPR-Cas9 knockout impeded the leukemic cell growth, survival, clonogenicity in vitro and leukemic burden in vivo. The absence of FASN minimally affected normal hematopoiesis but significantly attenuated or delayed leukemic progression in the oncogenic MLL-AF9 leukemia mouse model, leading to prolonged animal survival. By screening a library of platensimycin derivatives, we identified compound MS-C19 as a potent FASN inhibitor, which is superior to Orlistat or TVB-3166. Pharmaceutical targeting FASN by MS-C19 suppressed leukemic cell growth, clonogenicity and cell survival and induced myeloid differentiation in both leukemia cell lines and clinical AML blasts. Mechanistically, both MS-C19 insult and FASN deficiency triggered the activation of lysosomal and inflammatory gene expression. Depletion of Progranulin, a lysosomal and neuroinflammatory gene, in the presence of FASN depletion, significantly reverted the inhibition of leukemic cell growth, survival, and clonogenicity caused by FASN knockdown. Thus, mammalian FASN could be a therapeutic target for myeloid leukemia, and inhibition of FASN by the lead compound MS-C19 provides a promising approach for leukemia intervention.

No relevant conflicts of interest to declare.