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REVIEW ARTICLE

Metabolomics of healthy hematopoietic stem cells and leukemia stem cells

Gavin M. Traber1 ,  Emely A. Pacheco2 ,  Ansh Kumar1 ,  Edziu Franczak2 ,  Kelsey H. Fisher-Wellman2 ,  Kathleen M. Sakamoto1*
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1 Department of Pediatrics, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America
2 Department of Cancer Biology, Wake Forest University School of Medicine, Wake Forest University, Winston-Salem, North Carolina, United States of America
JCTR, 025320053 https://doi.org/10.36922/JCTR025320053
Received: 8 August 2025 | Revised: 6 September 2025 | Accepted: 9 September 2025 | Published online: 8 October 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

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.

Graphical abstract
Keywords
Hematopoietic stem cells
Leukemia stem cells
Metabolism
Metabolomics
Funding
Gavin M. Traber is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; TL1DK139565). Kathleen M. Sakamoto is funded by NIDDK (DK136961), the Leukemia and Lymphoma Society (R6518-23), the Pediatric Cancer Research Foundation (grant number: 858010), the Stanford Innovation Medicine Accelerator, Cure Childhood Cancer (grant number: 641095), and the Department of Defense (RA220017). Emely A. Pacheco and Kelsey H. Fisher- Wellman are supported by the National Cancer Institute (P01CA171983 and R01CA299332). Emely A. Pacheco, Edziu Franczak, and Kelsey H. Fisher-Wellman are supported by the National Cancer Institute (P01CA171983 and R01CA299332).
Conflict of interest
Kathleen M. Sakamoto is an Editorial Board Member of this journal, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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Journal of Clinical and Translational Research, Electronic ISSN: 2424-810X Print ISSN: 2382-6533, Published by AccScience Publishing
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