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

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. Brouwers-Vos, Eduardo M. Rego, Gerwin Huls, Marta Cascante and Jan Jacob Schuringa ()
Additional contact information
Ayşegül Erdem: University Medical Center Groningen, University of Groningen
Silvia Marin: Department of Biochemistry and Molecular Biology, Faculty of Biology
Diego A. Pereira-Martins: University Medical Center Groningen, University of Groningen
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
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
Jan Jacob Schuringa: University Medical Center Groningen, University of Groningen

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28737-3

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