A Deeply Quiescent Subset of CML LSC depend on FAO yet Avoid Deleterious ROS by Suppressing Mitochondrial Complex I

Area of Science:

• Cancer Stem Cell Biology
• Leukemia Pathogenesis
• Mitochondrial Metabolism

Background:

• Leukemia stem cells (LSC) drive cancer relapse and therapy resistance.
• Quiescent cancer stem cells (CSC) acquire mutations, complicating treatment.
• LSC share features with normal hematopoietic stem cells (HSC), hindering targeted elimination.

Purpose of the Study:

• Investigate LSC heterogeneity in chronic myelogenous leukemia (CML).
• Characterize the metabolic and transcriptional states of therapy-resistant LSC.
• Identify therapeutic strategies to eliminate quiescent LSC.

Main Methods:

• scRNA-sequencing and ATAC-seq on primary CML patient samples.
• Bioinformatics analysis of LSC heterogeneity.
• Single-cell metabolomic and Seahorse analyses to validate quiescent leukemia initiators (LI).

Main Results:

• CML LSC exist in two distinct functional states, with deeply quiescent LI suppressing mitochondrial complex I (MC-1) and utilizing fatty acid oxidation (FAO).
• Quiescent LI exhibit increased chromatin accessibility, indicative of primitive stemness.
• ICG-001, a CBP/β-catenin antagonist, promotes LSC differentiation, increases MC-1 expression, and resensitizes LSC to imatinib.

Conclusions:

• Deeply quiescent, therapy-resistant CSC can be eliminated by specific small molecule CBP/β-catenin antagonists.
• Targeting quiescent LSC represents a potential generalizable therapeutic strategy for leukemia cures.
• Understanding LSC heterogeneity is crucial for developing effective leukemia eradication protocols.