Very Long Chain Fatty Acid Synthesis is a Targetable Dependency in RAS Pathway Mutant Leukemia

Abstract Oncogenic RAS pathway mutations are associated with therapeutic resistance in acute myeloid leukemia, and identification of therapeutic vulnerabilities has been hindered by a lack of clinically relevant models and tractable ex vivo platforms. We utilize a bone marrow endothelial cell co-culture system to perform CRISPR screens on wild-type hematopoietic cells and isogenic leukemias with and without mutant Nras. We credentialed Elovl1, a very long chain fatty acid elongase, as a dependency in RAS pathway mutant leukemia using genetic and pharmacologic approaches. Metabolic and genetic studies in primary leukemias revealed that the fitness defect from Elovl1 loss reflects a mutant-specific dependency on de novo sphingolipid biosynthesis, specifically sphingomyelin production, as Sgms1 deletion phenocopies Elovl1 loss. Sphingomyelin-mediated generation of lipid rafts, key scaffolds for multiple signaling pathways, is essential to the survival of Nras-mutant AML cells. Our work leverages a new leukemia model to identify a targetable dependency in this treatment-refractory leukemia.