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

Autor: Erdem A; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.; Department of Biochemistry and Molecular Biology, Faculty of Biology, Avinguda Diagonal 643, 08028, Barcelona, Spain., Marin S; Department of Biochemistry and Molecular Biology, Faculty of Biology, Avinguda Diagonal 643, 08028, Barcelona, Spain.; CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III, 28029, Madrid, Spain.; Institute of Biomedicine of University of Barcelona, 08028, Barcelona, Spain., Pereira-Martins DA; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.; Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo, São Paulo, SP, Brazil., Cortés R; Department of Biochemistry and Molecular Biology, Faculty of Biology, Avinguda Diagonal 643, 08028, Barcelona, Spain., Cunningham A; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Pruis MG; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., de Boer B; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., van den Heuvel FAJ; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Geugien M; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Wierenga ATJ; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Brouwers-Vos AZ; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Rego EM; Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo, São Paulo, SP, Brazil., Huls G; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands., Cascante M; Department of Biochemistry and Molecular Biology, Faculty of Biology, Avinguda Diagonal 643, 08028, Barcelona, Spain.; CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III, 28029, Madrid, Spain.; Institute of Biomedicine of University of Barcelona, 08028, Barcelona, Spain., Schuringa JJ; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands. j.j.schuringa@umcg.nl.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Mar 01; Vol. 13 (1), pp. 1105. Date of Electronic Publication: 2022 Mar 01.
DOI: 10.1038/s41467-022-28737-3
Abstrakt: 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). PDK1 low AMLs are OXPHOS-driven, are enriched for leukemic granulocyte-monocyte progenitor (L-GMP) signatures, and are associated with FLT3-ITD and NPM1cyt mutations. PDK1 high AMLs however are OXPHOS low , 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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