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

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Erdem, Aysegul ; Marin, Silvia ; Pereira-Martins, Diego A. ; Cortes, Roldan ; Cunningham, Alan ; Pruis, Maurien G. ; de Boer, Bauke ; van den Heuvel, Fiona A. J. ; Geugien, Marjan ; Wierenga, Albertus T. J. ; Brouwers-Vos, Annet Z. ; Rego, Eduardo M. ; Huls, Gerwin ; Cascante, Marta ; Schuringa, Jan Jacob

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 13, n. 1, p. 16-pg., 2022-03-01.

Abstract

Acute myeloid leukemia (AML) is genetically a very heterogeneous disease. Here, Erdem et al. uncover heterogeneity in the metabolic landscape of AML and identify Pyruvate dehydrogenase kinase 1 (PDK1) as a targetable determinant of different metabolic states in distinct subtypes of AML. 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 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. (AU)

• FAPESP's process: 17/23117-1 - Evaluation of TP53/TP73 pathway in engraftment of acute promyelocytic leukemia cells in xenotransplantation model
• Grantee: Diego Antonio Pereira Martins
• Support Opportunities: Scholarships in Brazil - Doctorate