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The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia

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  • Ayşegül Erdem

    (University Medical Center Groningen, University of Groningen
    Department of Biochemistry and Molecular Biology, Faculty of Biology)

  • Silvia Marin

    (Department of Biochemistry and Molecular Biology, Faculty of Biology
    CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III
    Institute of Biomedicine of University of Barcelona)

  • Diego A. Pereira-Martins

    (University Medical Center Groningen, University of Groningen
    University of São Paulo)

  • Roldán Cortés

    (Department of Biochemistry and Molecular Biology, Faculty of Biology)

  • Alan Cunningham

    (University Medical Center Groningen, University of Groningen)

  • Maurien G. Pruis

    (University Medical Center Groningen, University of Groningen)

  • Bauke Boer

    (University Medical Center Groningen, University of Groningen)

  • Fiona A. J. Heuvel

    (University Medical Center Groningen, University of Groningen)

  • Marjan Geugien

    (University Medical Center Groningen, University of Groningen)

  • Albertus T. J. Wierenga

    (University Medical Center Groningen, University of Groningen
    University Medical Center Groningen, University of Groningen)

  • Annet Z. Brouwers-Vos

    (University Medical Center Groningen, University of Groningen)

  • Eduardo M. Rego

    (University of São Paulo)

  • Gerwin Huls

    (University Medical Center Groningen, University of Groningen)

  • Marta Cascante

    (Department of Biochemistry and Molecular Biology, Faculty of Biology
    CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III
    Institute of Biomedicine of University of Barcelona)

  • Jan Jacob Schuringa

    (University Medical Center Groningen, University of Groningen)

Abstract

Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and within individual patients. Here, we show that Pyruvate dehydrogenase kinase 1 (PDK1) acts as a targetable determinant of different metabolic states in acute myeloid leukemia (AML). PDK1low AMLs are OXPHOS-driven, are enriched for leukemic granulocyte-monocyte progenitor (L-GMP) signatures, and are associated with FLT3-ITD and NPM1cyt mutations. PDK1high AMLs however are OXPHOSlow, wild type for FLT3 and NPM1, and are enriched for stemness signatures. Metabolic states can even differ between genetically distinct subclones within individual patients. Loss of PDK1 activity releases glycolytic cells into an OXPHOS state associated with increased ROS levels resulting in enhanced apoptosis in leukemic but not in healthy stem/progenitor cells. This coincides with an enhanced dependency on glutamine uptake and reduced proliferation in vitro and in vivo in humanized xenograft mouse models. We show that human leukemias display distinct metabolic states and adaptation mechanisms that can serve as targets for treatment.

Suggested Citation

  • Ayşegül Erdem & Silvia Marin & Diego A. Pereira-Martins & Roldán Cortés & Alan Cunningham & Maurien G. Pruis & Bauke Boer & Fiona A. J. Heuvel & Marjan Geugien & Albertus T. J. Wierenga & Annet Z. Bro, 2022. "The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28737-3
    DOI: 10.1038/s41467-022-28737-3
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    1. Kristina Anderson & Christoph Lutz & Frederik W. van Delft & Caroline M. Bateman & Yanping Guo & Susan M. Colman & Helena Kempski & Anthony V. Moorman & Ian Titley & John Swansbury & Lyndal Kearney & , 2011. "Genetic variegation of clonal architecture and propagating cells in leukaemia," Nature, Nature, vol. 469(7330), pages 356-361, January.
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