Targeted in vivo CRISPR screen to identify metabolic vulnerabilities in pediatric ALL
The nutrient-sparse cerebrospinal fluid (CSF) poses a major challenge to spreading cancer cells. Despite this challenge, leukemia cells can spread to the CSF, requiring aggressive central nervous system (CNS)-directed treatment that can lead to dose-limiting neurotoxicity. Here we use 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 dietary intervention, significantly slows the growth of both systemic and CNS leukemia in a murine xenograft model. Mechanistically, copper depletion inhibits complex IV activity and nucleotide synthesis to slow the growth of leukemia cells. Furthermore, dietary depletion of copper combined with the standard-of-care therapy methotrexate (MTX) inhibits leukemia progression in cell-line and patient-derived xenograft models (PDXs). 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.