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Updated: May 30, 2025
Assessment of the Metabolic Profile of Primary Leukemia Cells
Published on: November 21, 2018
Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell
Monika Komza1,2,3, Jesminara Khatun1,2, Jesse D Gelles1,2
1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Abstract:
One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.
Insights
Inhibiting glucose uptake in leukemia cells forces them to rely on mitochondrial respiration for survival. This dependency, particularly in oncogenic RAS models, highlights a potential therapeutic vulnerability in acute myeloid leukemia (AML).
Area of Science:
- Cancer Metabolism
- Cellular Respiration
- Leukemia Pathogenesis
Background:
- Cancer cells exhibit high glucose metabolism for proliferation.
- Targeting glucose metabolism is a therapeutic strategy, but adaptations require further study.
- Understanding metabolic shifts upon glucose uptake inhibition is crucial for effective cancer therapy.
Purpose of the Study:
- To investigate metabolic adaptations in leukemia cells upon acute glucose uptake inhibition.
- To evaluate the role of mitochondrial oxidative phosphorylation in response to glucose transporter inhibition.
- To assess the therapeutic potential of targeting glucose metabolism in acute myeloid leukemia (AML).
Main Methods:
- Utilized KL-11743, a Class I glucose transporter inhibitor.
- Employed glycolytic leukemia cell lines and patient-derived induced pluripotent stem cell models.
- Assessed cellular respiration, glucose uptake, and glycolysis.
- Treated primary AML patient samples with KL-11743.
Main Results:
- KL-11743 significantly inhibited glucose uptake and glycolysis.
- Leukemia cells adapted by increasing mitochondrial oxidative phosphorylation, particularly Complex I function.
- Dependency on mitochondrial respiration was essential for survival, especially in oncogenic RAS AML models.
- Primary AML patient samples showed a similar reliance on mitochondrial respiration.
Conclusions:
- Acute glucose uptake inhibition induces a critical dependency on mitochondrial respiration in diverse leukemia models.
- Robust inhibition of glucose uptake is key to creating metabolic vulnerability.
- Mitochondrial respiration is a significant determinant of treatment success in AML.
- Targeting glucose transporters and exploiting the subsequent reliance on mitochondrial respiration presents a promising therapeutic strategy for AML.
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