SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA
Dongqing Yan 1, Anca Franzini # 1, Anthony D Pomicter # 1, Brayden J Halverson 1, Orlando Antelope 1, Clinton C Mason 2, Jonathan M Ahmann 1, Anna V Senina 1, Nadeem A Vellore 1, Courtney L Jones 3, Matthew S Zabriskie 1, Hein Than 4, Michael J Xiao 1, Alexandria van Scoyk 1, Ami B Patel 5, Phillip M Clair 1, William L Heaton 1, Shawn C Owen 6, Joshua L Andersen 7, Christina M Egbert 7, Julie A Reisz 8, Angelo D’Alessandro 3 8, James E Cox 9, Kevin C Gantz 1, Hannah M Redwine 1, Siddharth M Iyer 1, Jamshid S Khorashad 10, Nima Rajabi 11, Christian A Olsen 11, Thomas O’Hare 1 5, Michael W Deininger 12 5
We learned that the survival and development of many primary acute myeloid leukemia (AML) samples and cell lines, although not normal CD34 cells, rely on SIRT5, a lysine deacylase implicated in controlling multiple metabolic pathways. Reliance on SIRT5 is genotype-agnostic and reaches RAS- and p53-mutated AML. Outcome was comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a powerful and selective SIRT5 inhibitor. Apoptosis caused by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and a rise in mitochondrial superoxide that’s attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 like a vulnerability in AML.