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Very Long Chain Fatty Acid Synthesis is a Metabolic Dependency and Therapeutic Target in NRAS Mutant Leukemia

ABSTRACT: Acute myeloid leukemia is a lethal hematologic malignancy; oncogenic Nras mutations are consistent predictors of resistance to targeted therapies. Identification of therapeutic targets is hindered by a lack of clinically relevant models and amenable ex vivo platforms. We utilize a bone marrow endothelial cell co-culture system to perform CRISPR/Cas9 screens on wild-type cells and isogenic leukemias with and without oncogenic Nras. We identified Elovl1, a very long chain fatty acid (VLCFA) elongase, as an Nras selective leukemic dependency, both ex vivo and in vivo. Genetic studies in primary leukemias revealed the fitness defect from Elovl1 loss comes in part from disruption of sphingomyelin production, as sgRNAs targeting Sgms1 phenocopy Elovl1 loss. Sphingomyelin is an essential sphingolipid necessary for generating lipid rafts, key concentrating scaffolds for multiple signaling pathways required in Nras mutant AML. Our work leverages a novel leukemia model to validate a metabolic target in this treatment refractory leukemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE310778 | GEO | 2026/09/22

REPOSITORIES: GEO

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Very Long Chain Fatty Acid Synthesis is a Metabolic Dependency and Therapeutic Target in NRAS Mutant Leukemia

Project description:Acute myeloid leukemia is a lethal hematologic malignancy; oncogenic Nras mutations are consistent predictors of resistance to targeted therapies. Identification of therapeutic targets is hindered by a lack of clinically relevant models and amenable ex vivo platforms. We utilize a bone marrow endothelial cell co-culture system to perform CRISPR/Cas9 screens on wild-type cells and isogenic leukemias with and without oncogenic Nras. We identified Elovl1, a very long chain fatty acid (VLCFA) elongase, as an Nras selective leukemic dependency, both ex vivo and in vivo. Genetic studies in primary leukemias revealed the fitness defect from Elovl1 loss comes in part from disruption of sphingomyelin production, as sgRNAs targeting Sgms1 phenocopy Elovl1 loss. Sphingomyelin is an essential sphingolipid necessary for generating lipid rafts, key concentrating scaffolds for multiple signaling pathways required in Nras mutant AML. Our work leverages a novel leukemia model to validate a metabolic target in this treatment refractory leukemia.

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Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (i.e., DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided microarray data showing effect of R882H-mutated or WT DNMT3A on gene expression among HSPCs with NRAS G12D co-transduction.

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