New Tool Reveals Hidden Metabolic Weakness in Blood Cancers

Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, marked by poor survival rates and limited treatment options, especially in patients who do not respond to standard therapies. Despite advances in cancer genomics, most research has focused on single genes rather than how entire biological pathways interact to drive disease. This has left critical gaps in understanding why some leukemias are particularly resistant to treatment. A new computational approach now reveals how hidden pathway interactions sustain cancer growth and identifies a metabolic vulnerability that can selectively kill leukemia cells.

Researchers, led by Duke-NUS Medical School (Singapore), in collaboration with Duke University (Durham, NC, USA) and Inserm (Paris, France), have developed a novel computational mapping algorithm designed to analyze how large numbers of gene pathways interact within complex biological systems rather than examining genes in isolation. Using this tool, the team analyzed roughly 3,000 gene sets encompassing nearly 15,000 genes.

Image: Elevated Complex II levels were linked to treatment resistance and poorer survival in AML patients (Photo courtesy of Xu Lisheng/Duke-NUS Medical School)

The algorithm generated an integrated map of pathway interactions, allowing researchers to identify coordinated biological processes that support cancer cell survival, particularly those involved in energy metabolism and biosynthesis. The pathway analysis revealed an unexpected link between cellular energy metabolism and purine synthesis in leukemia cells. Specifically, the researchers identified mitochondrial Complex II as a critical metabolic hub that enables AML cells to generate purines, which are essential building blocks for DNA and RNA synthesis.

Blocking Complex II disrupted purine production, leading to selective cancer cell death while sparing normal cells, which could compensate through alternative metabolic pathways. These findings, validated in preclinical models and published in Nature Metabolism, showed that higher levels of Complex II activity are associated with increased treatment resistance and poorer survival in AML patients, suggesting that Complex II could serve as both a therapeutic target and a biomarker.

High-risk and drug-resistant AML patients may particularly benefit from therapies that inhibit this metabolic pathway. Going forward, the researchers plan to identify new drug candidates targeting Complex II, explore additional metabolic vulnerabilities across other blood cancers and solid tumors, and develop web-based and machine-learning tools to predict which patients are most likely to benefit from metabolism-focused treatments.

“Our pre-clinical trials showed dramatic tumor regression and extended survival when targeting Complex II, suggesting that this could translate into meaningful clinical benefits,” said Dr. Alexandre Puissant, the paper's senior author.

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Duke University
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