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<p>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 <i>SLC31A1</i> 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.</p>

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Copper depletion boosts CNS leukemia therapy by inhibiting nucleotide synthesis through impairment of mitochondrial complex IV activity

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Alan Y. L. Wong,
  • Jacob W. Myers,
  • Gyan Prakash,
  • Alice Ma,
  • Jeannette R. Brook,
  • Boryana Petrova,
  • Baran Bulut,
  • Ralph White III,
  • Catherine Merz,
  • Maeve de Souza,
  • Adam G. Maynard,
  • Peng Wang,
  • Amy Yu,
  • Nancy K. Pohl,
  • Michal Weitman,
  • Lewis B. Silverman,
  • Kimberly Stegmaier,
  • L. Stirling Churchman,
  • Peter D. Cole,
  • Donita C. Brady,
  • Naama Kanarek

摘要

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.