Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II
Open accessAbstract
We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP, and leading to LSC death. Given the role of cysteine in driving LSC energy production, we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme, we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism, and that targeting this axis may represent a useful therapeutic strategy.
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Depleting GSH through exogenous cyst(e)ine degradation with cyst(e)inase demonstrates a similar mechanism of action in AML stem cells.
“depleting GSH through exogenous cyst(e)ine degradation with cyst(e)inase demonstrated a similar MoA in AML stem cells (47).”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [47]
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Self-citationInhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells
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Birsen, R., Larrue, C., Decroocq, J., Johnson, N., Guiraud, N., Gotanegre, M., Cantero-Aguilar, L., Grignano, E., Huynh, T., Fontenay, M., et al. (2021) · Haematologica · doi:10.3324/haematol.2020.259531 · Cited by 182 · see citing works
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“Moreover, depleting GSH through exogenous cyst(e)ine degradation with cyst(e)inase demonstrated a similar MoA in AML stem cells ( 47 ).”
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- Authors
- Jones, C. L., Stevens, B. M., D’Alessandro, A., Culp-Hill, R., Reisz, J. A., Pei, S., Gustafson, A., Khan, N., DeGregori, J., Pollyea, D. A., & Jordan, C. T.
- Affiliations
- Division of Hematology and
- University of Colorado Denver (US)
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2019-07-25
- Volume
- 134
- Issue
- 4
- Pages
- 389-394
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC6659257
- OpenAlex
- W2945249631
- Cited by
- 158
- References
- 13
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 18 · 2023: 17 · 2022: 31 · 2021: 31 · 2020: 24 · 2019: 7
- FWCI
- 16.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Aeglea BioTherapeutics
- National Cancer Institute (R01CA200707)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- cysteine depletion, leukemia stem cells, acute myeloid leukemia, glutathione synthesis, glutathionylation, oxidative phosphorylation, amino acid metabolism, energy metabolism, hematopoietic stem and progenitor cells
- MeSH terms
- Adenosine Triphosphate, Cysteine, Energy Metabolism, Glutathione, Humans, Oxidation-Reduction, Oxidative Phosphorylation, Succinate Dehydrogenase, Neoplastic Stem Cells, Biomarkers, Leukemia, Myeloid, Acute, Reactive Oxygen Species, Electron Transport Complex II
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