Breakthrough study reveals key mechanism behind therapy-resistant leukemia stem cells

A team of researchers led by Dr. Nyam-Osor Chimge and Dr. Michael Kahn has uncovered a critical survival mechanism in therapy-resistant leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Published in Current Molecular Pharmacology, the study reveals that deeply quiescent LSCs avoid oxidative stress by suppressing mitochondrial complex I (MC-1) while relying on fatty acid oxidation (FAO) for energy.

Using single-cell RNA sequencing and functional metabolomic profiling, the team identified a subset of LSCs—termed "leukemia initiators" (LI)—that exhibit extreme quiescence and low metabolic activity. "These cells essentially 'hide' by shutting down MC-1, which minimizes reactive oxygen species (ROS) and allows them to persist despite therapy," explained Dr. Chimge.

The study highlights the potential of the small molecule ICG-001, a CBP/β-catenin antagonist, to force LI differentiation and re-sensitize them to tyrosine kinase inhibitors (TKIs) like imatinib. "ICG-001 disrupts the quiescence program, reactivates MC-1, and restores susceptibility to treatment," said Dr. Kahn. The findings suggest a novel therapeutic strategy to eradicate residual LSCs and prevent relapse in CML patients.