Reactive oxygen species define leukemia stem cell identity in pediatric acute myeloid leukemia.
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Standard chemotherapy effectively induces complete remission in most children with acute myeloid leukemia (AML), however relapse remains the main cause of treatment failure. Leukemia stem cells (LSCs) are proposed to constitute a therapy-resistant reservoir driving disease recurrence, but their reliable identification remains unresolved. We explored intracellular reactive oxygen species (ROS) levels in pediatric AML at diagnosis and sorted ROS-low (RL) and ROS-high (RH) cell fractions. We found that RL cells exhibited increased quiescence, sustained serial colony-forming capacity and engraftment in mice when compared to the RH fraction. Moreover, in a 3D niche model, RL cells preferentially localized to hypoxic regions and were resistant to cytarabine, altogether indicating enrichment for functional LSCs. Transcriptomic analyses revealed enrichment of stemness, adhesion and niche-interaction programs in RL cells, alongside downregulation of mitochondrial and oxidative phosphorylation pathways. Consistently, RL cells displayed reduced oxygen consumption and ATP production, together with remodeled cristae structure despite preserved mitochondrial mass. Paradoxically, complex I inhibition selectively impaired RL cell viability, indicating a dependency on oxidative phosphorylation. Using RL transcriptome, we derived a gene signature that, when applied to single-cell RNA-sequencing data of pediatric AML cases, identified LSCs within the bulk regardless of differentiation status, and showed significant prognostic value. Finally, transcriptional program trajectory indicated that RL fraction contributed to generate the whole AML bulk, whereas gene mutations were maintained in RL and RH cells. Overall, this ROS-based strategy represents a new tool to isolate stem cells transcending traditional markers, and identifies novel clinically relevant vulnerabilities to target LSCs.