AI Article Synopsis
- Deregulated oxidative metabolism is a key feature of leukaemia, which affects how cancer cells use energy.
- Tyrosine kinase inhibitors like imatinib help people with chronic myeloid leukaemia (CML), but they don't completely get rid of the difficult-to-treat leukemic stem cells (LSCs).
- Researchers found that LSCs have a unique way of using a nutrient called pyruvate, which could be targeted with new treatments to make CML cells more sensitive to imatinib.
Article Abstract
Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics reveals that deregulated pyruvate anaplerosis is not affected by imatinib. Encouragingly, genetic ablation of pyruvate anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10435520 | PMC |
| http://dx.doi.org/10.1038/s41467-023-40222-z | DOI Listing |
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