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Nat Commun. 2018 Sep 12;9(1):3694. doi: 10.1038/s41467-018-05984-x.

Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes.

Author information

1
Division of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
2
Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO, 80045, USA.
3
Department of Pediatrics, University of Colorado Denver, Aurora, CO, 80045, USA.
4
Division of Hematology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, 80045, USA. craig.jordan@ucdenver.edu.

Abstract

Myelodysplastic syndrome (MDS) is a chronic hematologic disorder that frequently evolves to more aggressive stages and in some cases leads to acute myeloid leukemia (AML). MDS arises from mutations in hematopoietic stem cells (HSCs). Thus, to define optimal therapies, it is essential to understand molecular events driving HSC pathogenesis. In this study, we report that during evolution of MDS, malignant HSCs activate distinct cellular programs that render such cells susceptible to therapeutic intervention. Specifically, metabolic analyses of the MDS stem cell compartment show a profound activation of protein synthesis machinery and increased oxidative phosphorylation. Pharmacological targeting of protein synthesis and oxidative phosphorylation demonstrated potent and selective eradication of MDS stem cells in primary human patient specimens. Taken together, our findings indicate that MDS stem cells are reliant on specific metabolic events and that such properties can be targeted prior to the onset of clinically significant AML, during antecedent MDS.

PMID:
30209285
PMCID:
PMC6135858
DOI:
10.1038/s41467-018-05984-x
[Indexed for MEDLINE]
Free PMC Article

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