Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells.
Kevin M RattiganZuzana BrabcovaDaniele SarnelloMartha M ZarouKiron RoyRyan KwanLucie de BeauchampAmy DawsonAngela IannicielloAhmed KhalafEric R KalkmanMary T ScottKaren M DunnDavid SumptonAlison M MichieMhairi CoplandSaverio TarditoEyal GottliebG Vignir HelgasonPublished in: Nature communications (2023)
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.
Keyphrases
- chronic myeloid leukemia
- stem cells
- newly diagnosed
- end stage renal disease
- climate change
- oxidative stress
- acute myeloid leukemia
- mass spectrometry
- ejection fraction
- dendritic cells
- induced apoptosis
- peritoneal dialysis
- bone marrow
- gene expression
- tyrosine kinase
- signaling pathway
- acute lymphoblastic leukemia
- prognostic factors
- high throughput
- cell death
- atrial fibrillation
- patient reported outcomes
- advanced non small cell lung cancer