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

Author

Listed:
  • Brett M. Stevens

    (University of Colorado School of Medicine)

  • Nabilah Khan

    (University of Colorado School of Medicine)

  • Angelo D’Alessandro

    (University of Colorado Denver)

  • Travis Nemkov

    (University of Colorado Denver)

  • Amanda Winters

    (University of Colorado Denver)

  • Courtney L. Jones

    (University of Colorado School of Medicine)

  • Wei Zhang

    (University of Colorado School of Medicine)

  • Daniel A. Pollyea

    (University of Colorado School of Medicine)

  • Craig T. Jordan

    (University of Colorado School of Medicine)

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.

Suggested Citation

  • Brett M. Stevens & Nabilah Khan & Angelo D’Alessandro & Travis Nemkov & Amanda Winters & Courtney L. Jones & Wei Zhang & Daniel A. Pollyea & Craig T. Jordan, 2018. "Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05984-x
    DOI: 10.1038/s41467-018-05984-x
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    Cited by:

    1. Lina Liu & Ana Vujovic & Nandan P. Deshpande & Shashank Sathe & Govardhan Anande & He Tian Tony Chen & Joshua Xu & Mark D. Minden & Gene W. Yeo & Ashwin Unnikrishnan & Kristin J. Hope & Yu Lu, 2022. "The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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