Pyruvate Anaplerosis Is a Targetable Vulnerability in Persistent Leukaemic Stem Cells

Authors

Kevin M Rattigan
Zuzana Brabcova
Daniele Sarnello
Martha M Zarou
Kiron Roy
Ryan Kwan
Lucie de Beauchamp
Amy Dawson
Angela Ianniciello
Ahmed Khalaf
Eric R Kalkman
Mary T Scott
Karen Dunn
David Sumpton
Alison M Michie
Mhairi Copland
Saverio Tardito
Eyal Gottlieb
G Vignir Helgason

Publication Date

8-17-2023

Journal

Nature Communications

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.

Keywords

Humans, Pyruvic Acid, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Acclimatization, Biological Assay

Comments

Supplementary Materials

PMID: 37591854