Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity
Menée à l'aide de lignées cellulaires, de modèles murins et de xénogreffes de leucémie lymphoblastique aiguë, cette étude met en évidence un mécanisme par lequel une déplétion en cuivre améliore l'efficacité du traitement de la leucémie du système nerveux central en inhibant la synthèse des nucléotides via l'altération de l'activité du complexe mitochondrial IV
The nutrient-sparse cerebrospinal fluid (CSF) poses a major challenge to spreading cancer cells. Despite this challenge, leukemia cells spread to the CSF, requiring aggressive central nervous system (CNS)-directed treatment that can lead to neurotoxicity. Here we used a targeted in vivo CRISPR screen to identify nutritional dependencies of systemic and CNS acute lymphoblastic leukemia (ALL). We show that copper depletion, either by genetic deletion of the transporter SLC31A1 or by dietary intervention, slows the growth of both systemic and CNS leukemia in a xenograft model. Mechanistically, copper depletion inhibits complex IV and nucleotide synthesis to slow the growth of leukemia cells. Furthermore, dietary depletion of copper combined with the standard-of-care therapy methotrexate inhibits leukemia progression in cell-line-derived and patient-derived xenograft models. Our findings identify copper as an actionable micronutrient to disrupt nucleotide synthesis in ALL and proposes copper depletion as a way to boost leukemia therapy in the hard-to-treat CNS.
Nature Cancer , article en libre accès, 2026