摘要：SummaryMutations in RAS pathway genes are highly prevalent in acute lymphoblastic leukemia (ALL). However, the effects of RAS mutations on ALL cell growth have not been experimentally characterized, and effective RAS-targeting therapies are being sought after. Here, we found that Reh ALL cells bearing the KRAS-G12D mutation showed increased proliferation ratesin vitrobut displayed severely compromised growth in mice. Exploring this divergence, proliferation assays with multiple ALL cell lines revealed that the KRAS-G12D rewired methionine and arginine metabolism. Isotope tracing results showed that KRAS-G12D promotes catabolism of methionine and arginine to support anabolism of polyamines and proline, respectively. Chemical inhibition of polyamine biosynthesis selectively killed KRAS-G12D B-ALL cells. Finally, chemically inhibiting AKT/mTOR signaling abrogated the altered amino acid metabolism and strongly promoted thein vivogrowth of KRAS-G12D cells in B-ALL xenograft. Our study thus illustrates how hyperactivated AKT/mTOR signaling exerts distinct impacts on hematological malignancies vs. solid tumors.Graphical abstractDisplay OmittedHighlights•Reh ALL cells bearing KRAS-G12D displayed compromised growth in mice•KRAS-G12D rewires methionine and arginine metabolism in B-ALL cells•Chemically inhibiting polyamine biosynthesis can potently kill KRAS-G12D ALL cells•Moderate mTOR inhibition can rescuein vivogrowth of KRAS-G12D B-ALL cellsBiological sciences; Biochemistry; Molecular biology
