Background: Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and sustain life-long hematopoiesis by balancing quiescence, self-renewal, and differentiation. A key feature distinguishing quiescent HSCs from their activated counterparts is a shift in their metabolic profile, including changes in glycolytic flux and mitochondrial oxidative metabolism. Disruption of HSC homeostasis can lead to hematologic diseases such as BM failure, clonal hematopoiesis, or oncogenic transformation into leukemia stem cells (LSCs). Similar to HSCs, LSCs retain stem-like characteristics but acquire malignant features, including drug resistance and a reprogrammed metabolism, which results in distinct metabolic profiles that contribute to their pathogenesis. Aim: This review summarizes the key metabolic characteristics distinguishing healthy quiescent and active HSCs from oncogenic LSCs. In addition, we highlight modern tools for investigating the metabolome, which enable the identification of novel metabolites, metabolic interactions, pathways, and potential targets for diagnosis or therapeutic intervention in hematologic diseases. Conclusion: Metabolic regulation is essential for maintaining HSC quiescence, self-renewal, and lineage commitment, whereas its disruption often underlies oncogenic transformation into LSCs. Advances in metabolic profiling reveal key differences between healthy HSCs and LSCs and identify LSC vulnerabilities that sustain survival and therapeutic resistance. Targeting these hijacked metabolic pathways may facilitate the development of LSC-specific treatment while preserving normal hematopoiesis. Further investigation of stem cell metabolism will be critical for translating these insights into effective treatments for hematologic malignancies. Relevance for patients: Understanding the metabolic profiles of healthy HSCs and LSCs can facilitate the development of innovative techniques, technologies, and therapeutics. These advances can be applied to the identification, treatment, and prevention of hematologic disease. By elucidating the metabolome of LSCs, therapies can be designed to selectively target their unique metabolic pathways, dependencies, and resistance mechanisms.
Traber et al. (2025) studied this question.