Page 63 - JCTR-11-5

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

through GLUT1, its contribution to ATP production and regulating LSC localization. As discussed in Section
2,27
remains undefined. Moreover, other studies reported that 2.2, quiescent HSCs downregulate mitochondrial function
dual inhibition of GLUT1 and OXPHOS is required to fully to minimize the negative effects of ROS accumulation. In
eliminate LSCs in vivo. Although FAO remains a viable contrast, LSCs maintain robust mitochondrial metabolism
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metabolic target, its precise contribution relative to other even under hypoxic conditions in the BM niche. In
substrates, such as glutamine, remains an open question. xenograft studies, AML LSCs that survive cytarabine
Further investigation is needed to explore the specific treatment retain high mitochondrial activity and strong
fuel preferences of LSCs and to identify context-specific BM adhesion capacity, underscoring their ability to resist
therapeutic vulnerabilities across leukemia subtypes. therapy through persistent mitochondrial function.
107
Unlike quiescent HSCs, LSCs maintain ROS at levels
3.2. Role of nutrient-sensing pathways in HSCs and conducive to self-renewal and mitigate ROS-induced
LSCs
damage by upregulating antioxidant defenses, including
In addition to metabolic pathways, evidence suggests that non-enzymatic antioxidant systems similar to those of
nutrient-sensing pathways also play a role in regulating active HSCs. 14,75,83,88
stem cell metabolism. 5,98,99 These include the AMPK and In addition to intrinsic metabolic adaptations,
mechanistic target of rapamycin complex 1 (mTORC1) LSCs that exhibit resistance to chemotherapy exploit
signaling pathways. In quiescent HSCs, suppression of extrinsic cues from the microenvironment. Adipocyte-
28
mTORC1 activity is essential for maintaining dormancy
and preventing premature differentiation by reducing rich BM provides LSCs with an exogenous source of
protein synthesis and inhibiting cell growth. 5,100 Conversely, fatty acids to support FAO and sustain mitochondrial
85
AMPK activation plays a pivotal role in preserving energy respiration. Furthermore, LSCs actively remodel their
homeostasis during metabolic stress by promoting catabolic microenvironment by engaging in stromal interactions and
processes such as FAO and glycolysis to generate ATP, while altering chemokine gradients, thereby promoting niche
28
inhibiting anabolic processes to preserve energy. This retention and therapeutic evasion. Through the increased
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balance supports both quiescence and the long-term self- expression of ABC transporters (e.g., ABCB1, ABCC1,
renewal capacity of HSCs under physiological conditions. and ABCG2), LSCs efflux chemotherapy drugs, reducing
treatment efficacy and contributing to drug resistance
In LSCs, however, this balance between nutrient- across multiple cancers. 1,108 In LSCs, oncogenic drivers
signaling pathways—namely, mTORC1 and AMPK—is such as c-MYC enhance the activity of these transporters,
reprogrammed. The mTORC1 pathway acts as a central enabling more efficient drug efflux and thereby increasing
regulator of anabolic metabolism, enhancing amino chemoresistance and relapse potential. These strategies
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102
acid uptake, protein synthesis, and RNA and DNA highlight the diverse resistance mechanisms by which
biosynthesis. In contrast, AMPK inhibits fat and protein LSCs resist hypoxia and chemotherapy, suggesting that
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biosynthesis and promotes FAO and glycolysis to maintain targeting both intrinsic metabolic programs and extrinsic
energy balance. Previous research has shown that niche interactions may be necessary to overcome LSC-
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chemical activation of AMPK in CD34 AML cells inhibits mediated relapse.
+
mTORC1 signaling and enhances sensitivity to cytarabine
and idarubicin, suggesting that therapeutic manipulation 3.4. Genomic alterations in LSCs
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of these pathways can impair LSC maintenance and viability. Metabolic changes in LSCs do not occur passively but
Similar observations have been reported in solid tumor are instead typically driven by genetic mutations or
models, where AMPK activation reduces cancer stem modifications that actively influence cellular energy
cell survival. Collectively, these findings underscore the
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conserved yet opposing roles of AMPK and mTOR1 signaling processing. In chronic lymphocytic leukemia, although
in regulating stemness. Moreover, as nutrient availability and genetic mutations do not directly alter the expression
metabolic signaling pathways are tightly linked to stemness of genes involved in metabolic pathways, STAT3
and therapeutic resistance, targeting these pathways offers a becomes constitutively activated, with reduced levels
promising strategy for selectively eliminating LSCs without of microRNA-125 playing a major role. This ultimately
compromising normal hematopoiesis. promotes the transition of LSCs toward more efficient fatty
acid utilization for energy production. 110
3.3. Mechanisms of adaptation to hypoxia and The HIF pathway helps healthy blood stem cells remain
chemoresistance in a glycolysis-dependent resting state; however, its role
Previous reviews have highlighted that the hypoxic BM in LSCs is more complex. 111,112 Although LSCs reside in
niche plays a significant role in maintaining HSC quiescence hypoxic niches, elimination of HIF-1α accelerates disease

Volume 11 Issue 5 (2025) 57 doi: 10.36922/JCTR025320053