Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells

Area of Science:

• Oncology
• Metabolic pathways
• Leukemia stem cell biology

Background:

• Deregulated oxidative metabolism is characteristic of leukemia.
• Tyrosine kinase inhibitors (TKIs) improve survival in chronic myeloid leukemia (CML) but do not eliminate leukemic stem cells (LSCs).
• The metabolic state of TKI-treated CML LSCs remains unclear.

Purpose of the Study:

• Investigate metabolic adaptations in patient-derived CML LSCs.
• Determine if TKI treatment affects LSC metabolic deregulation.
• Identify potential therapeutic targets in CML LSCs.

Main Methods:

• Multi-omics datasets generation using clinically relevant assays.
• Stable isotope-assisted metabolomics.
• Genetic ablation of pyruvate anaplerosis.
• Pre-clinical CML models using MSDC-0160, an MPC1/2 inhibitor.

Main Results:

• CML LSCs show increased pyruvate anaplerosis via elevated mitochondrial pyruvate carrier 1/2 (MPC1/2) and pyruvate carboxylase (PC) activity.
• Imatinib treatment reversed some metabolic reprogramming but did not affect pyruvate anaplerosis.
• Genetic inhibition of pyruvate anaplerosis sensitized CML cells to imatinib.
• MSDC-0160 inhibited pyruvate anaplerosis and targeted imatinib-resistant CML LSCs.

Conclusions:

• Pyruvate anaplerosis is a persistent metabolic vulnerability in CML LSCs, unaffected by imatinib.
• Targeting pyruvate anaplerosis, particularly with MPC inhibitors like MSDC-0160, offers a potential therapeutic strategy for imatinib-resistant CML.
• This highlights a novel therapeutic avenue for eradicating residual CML disease.