Metabolomics of healthy hematopoietic stem cells and leukemic stem cells

Background. Hematopoietic stem cells (HSCs) reside in the bone marrow and are responsible for the life-long production of blood cells by balancing quiescence, self-renewal, and differentiation. A major feature distinguishing quiescent HSCs from their activated counterparts is a shift in the metabolic profile including changes in glycolytic flux and mitochondrial oxidative metabolism. Disruptions to HSC homeostasis can lead to hematologic diseases such as bone marrow failure or clonal hematopoiesis and even oncogenic transformation to form leukemic stem cells (LSCs). Like that of HSCs, LSCs retain stem-like characteristics but also gain features of malignancy including drug resistance and a hijacked metabolism that exhibit distinct metabolic profiles that can underlie their pathogenesis. The aim of this review is to summarize the key metabolic characteristics that distinguish healthy quiescent and active HSCs as well as oncogenic LSCs. Here we also explore the modern tools used to investigate the metabolome and how they can reveal novel metabolites, metabolic interactions and pathways, and targets for diagnosis or therapeutic intervention of hematologic diseases. Understanding and interrogating changes to the metabolic profiles of healthy and leukemic stem cells may lead to the development of innovative techniques, technologies, and therapeutics. In turn, these advances can be used for the identification, treatment, and prevention of hematologic disease. By better understanding their metabolome, therapies can be designed to target the unique metabolic pathways, dependencies, and resistance mechanisms of LSCs.