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

Brett M. Stevens, Nabilah Khan, Angelo D’Alessandro, Travis Nemkov, Amanda Winters, Courtney L. Jones, Wei Zhang, Daniel A. Pollyea and Craig T. Jordan ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05984-x

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