Page 58 - JCTR-11-5

Journal of Clinical and
Translational Research Metabolism of healthy and leukemic stem cells

Figure 1. Healthy HSC metabolism. A graphical depiction of a healthy HSC located within the hypoxic BM niche, which creates an ideal environment for
stabilizing HIF-1 . The increased expression of HIF-1α reinforces the preference of quiescent HSCs for anaerobic glycolysis and minimizes the use of
α 1,2,21
mitochondrial OXPHOS and the production of destructive ROS. 1,2,21 Decreased ROS production provides protection from genetic instability, metabolic
stress, and functional decline of the HSC induced by ROS, while helping maintain cell quiescence. Alongside increased glucose uptake for anaerobic
1,2
glycolysis, quiescent HSCs also rely on FAO, thereby reducing reliance on OXPHOS. However, OXPHOS is not eliminated but instead maintained
5,22
at low levels with the help of SIRT7-mediated inhibition of NRF1, which suppresses mitochondrial biogenesis, function, and OXPHOS to reduce ROS
accumulation. 1,23,24 Although OXPHOS is largely suppressed, mitochondrial homeostasis in healthy quiescent HSCs is maintained through the balance of
mitochondrial biogenesis, fusion, fission, and mitophagy, collectively termed “mitochondrial dynamics.” 5,9,10
Abbreviations: BM: Bone marrow; FAO: Fatty acid oxidation; HIF-1α: Hypoxia-inducible factor 1α; HSC: Hematopoietic stem cell; NRF1: Nuclear
regulatory factor 1; OXPHOS: Oxidative phosphorylation; ROS: Reactive oxygen species; SIRT7: Sirtuin 7.

Table 1. Key metabolic themes across normal hematopoietic stem cells and leukemia stem cells
Metabolic theme Quiescent normal HSCs Active normal HSCs LSCs References
Glycolysis Increased glycolysis Moderate glycolysis to support Aerobic glycolysis (i.e., Warburg effect), in 5,14
OXPHOS oxygen-rich conditions
Mitochondrial Low respiratory flux, minimal Increased respiratory flux, enhanced Enlarged mitochondrial mass, respiratory 5,14,25
respiration OXPHOS OXPHOS to support proliferation flux, and OXPHOS; reliance on
mitochondrial metabolism for survival
FAO Enhanced FAO to support Sustained FAO to meet energy demands Increased FAO utilization, crucial for 5,22,26
energy demand and maintain during activation survival and proliferation
stemness
ROS levels and Low ROS levels, robust Increased mitochondrial-derived ROS Elevated ROS levels, dependence on 5,6,10
redox state antioxidant systems levels, balanced by antioxidant responses antioxidant systems for survival (e.g.,
(enzymatic/non-enzymatic) glutathione pathway)
Hypoxia and Hypoxic niche preference, Reduced HIF-1α stabilization Increased stabilization of HIF-1α and 6,21,27,28
HIF-1α pathway stabilized HIF-1α to maintain upon exiting the hypoxic niche and downstream pathways supporting survival,
quiescence proliferation/differentiation drug resistance, and leukemia progression
Abbreviations: FAO: Fatty acid oxidation; HIF-1α: Hypoxia-inducible factor 1α; HSC: Hematopoietic stem cell; LSC: Leukemia stem cell;
OXPHOS: Oxidative phosphorylation; ROS: Reactive oxygen species.

Volume 11 Issue 5 (2025) 52 doi: 10.36922/JCTR025320053