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- Title
Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells.
- Authors
Rattigan, Kevin M.; Brabcova, Zuzana; Sarnello, Daniele; Zarou, Martha M.; Roy, Kiron; Kwan, Ryan; de Beauchamp, Lucie; Dawson, Amy; Ianniciello, Angela; Khalaf, Ahmed; Kalkman, Eric R.; Scott, Mary T.; Dunn, Karen; Sumpton, David; Michie, Alison M.; Copland, Mhairi; Tardito, Saverio; Gottlieb, Eyal; Vignir Helgason, G.
- 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. The persistence of leukemic stem cells (LSCs) is known to limit the success of imatinib in patients with chronic myeloid leukaemia (CML). Here, the authors identify a reliance of these persisting LSCs on pyruvate carboxylase mediated pyruvate anaplerosis for survival after imatinib and demonstrate the therapeutic efficacy of targeting this using an inhibitor of mitochondrial pyruvate carrier.
- Subjects
STEM cells; PYRUVATES; CHRONIC myeloid leukemia; PROTEIN-tyrosine kinase inhibitors; PYRUVATE carboxylase; IMATINIB
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40222-z