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 de Boer, Fiona A J van den Heuvel, Marjan Geugien, Albertus T J Wierenga, Annet Z Brouwers-Vos, Eduardo M Rego, Gerwin Huls, Marta Cascante, Jan Jacob Schuringa*

*Bijbehorende auteur voor dit werk

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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.

Originele taal-2English
Artikelnummer1105
Aantal pagina's16
TijdschriftNature Communications
Volume13
Nummer van het tijdschrift1
DOI's
StatusPublished - 1-mrt-2022

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