ArticleNature metabolism2025
Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
Article in Nature metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.bioRxiv : the preprint server for biology · 2026Article
- Succinate calls a time-out on pyrimidine biosynthesis.Nature metabolism · 2026Article
- Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.The Biochemical journal · 2026Review
- datadrivenhypothesis.org: A resource for metabolic gene discovery through integrated pathway co-essentiality mapping.bioRxiv : the preprint server for biology · 2026Article
- Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADPFree radical biology & medicine · 2025Review
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Abstract
Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.
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