Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia
Year: 2025
Type: article
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.
Source: Nature Metabolism
Authors: Amy E. Stewart, Derek K. Zachman, Pol Castellano-Escuder, Lois M. Kelly, Ben Zolyomi, Michael D. I. Aiduk, Christopher D. Delaney, Ian C. Lock, Claudie Bosc, John Bradley, Shane T. Killarney, J. Darren Stuart, Paul A. Grimsrud, Olga R. Ilkayeva, Christopher B. Newgard, Navdeep S. Chandel, Alexandre Puissant, Kris C. Wood, Matthew D. Hirschey
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: G1174881085, G1185693225, G1705852268, G2369817142, G263690696, G2645538083, Studies on the Mechanisms by which SIRT5 Regulates Aging and Disease, G2986513518, Defining the Mechanistic Determinants of Response to Selective Electron Transport Chain Inhibition in Cancer, Metabolic regulation of oxidative phosphorylation in pediatric AML relapse, G5879378563, Lineage-specific signaling and targeting of PI3K gamma in myeloid malignancies, G6404540076, G6776764549, G746502960, Unified Program for Therapeutics in Children, Cancer Center Support Grant (CCSG)
OpenAlex ID: W4417031754