Targeting Fatty Acid Metabolism Abrogates the Differentiation Blockade in Preleukemic Cells

Abstract Metabolism plays a key role in the maintenance of normal hematopoietic stem cells (HSC) and in the development of leukemia. A better understanding of the metabolic characteristics and dependencies of preleukemic cells could help identify potential therapeutic targets to prevent leukemic transformation. As AML1–ETO, one of the most frequent fusion proteins in acute myeloid leukemia that is encoded by a RUNX1::RUNX1T1 fusion gene, is capable of generating preleukemic clones, in this study, we used a conditional Runx1::Runx1t1 knockin mouse model to evaluate preleukemic cell metabolism. AML1–ETO expression resulted in impaired hematopoietic reconstitution and increased self-renewal ability. Oxidative phosphorylation and glycolysis decreased significantly in these preleukemic cells accompanied by increased HSC quiescence and reduced cell cycling. Furthermore, HSCs expressing AML1–ETO exhibited an increased requirement for fatty acids through metabolic flux. Dietary lipid deprivation or loss of the fatty acid transporter FATP3 by targeted deletion using CRISPR/Cas9 partially restored differentiation. These findings reveal the unique metabolic profile of preleukemic cells and propose FATP3 as a potential target for disrupting leukemogenesis. Significance: Fatty acid metabolism is required for maintenance of preleukemic cells but dispensable for normal hematopoiesis, indicating that dietary lipid deprivation or inhibiting fatty acid uptake may serve as potential strategies to prevent leukemogenesis.