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

Ayşegül Erdem,Silvia Marin,Albertus T J Wierenga,Annet Z Brouwers-Vos,Fiona A J Van Den Heuvel,Eduardo M Rego,Marjan Geugien,Bauke De Boer,Marta Cascante,Roldán Cortés,Gerwin Huls,Diego A Pereira-Martins,Jan Jacob Schuringa,Alan Cunningham,Maurien G Pruis

doi:10.1038/s41467-022-28737-3

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.

Highlights

Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and within individual patients
Our full label-free quantitative proteome analyses within the CD34+ fraction[7] in primary acute myeloid leukemia (AML) patient samples (n = 42, Supplementary Data 1) compared to healthy CD34+ hematopoietic stem/progenitor cells revealed that downregulated proteins in AML were significantly enriched for gene ontology (GO) terms associated with myeloid commitment, while upregulated proteins were enriched for GO terms “RNA splicing”, “ribosome biogenesis” and various metabolic processes (Fig. 1a and Supplementary Data 2)
Among the upregulated proteins we identified several that are part of the electron chain transport, potentially linked to increased mitochondrial respiration, but we identified Pyruvate dehydrogenase kinase 1 (PDK1) to be among the upregulated proteins (Supplementary Data 2), which would potentially lead to a more glycolytic metabolism as PDK1 has been shown to act as the gatekeeper of glycolysis by phosphorylating and thereby inactivating Pyruvate Dehydrogenase (PDH), subsequently preventing the conversion of pyruvate into acetyl-CoA and TCA cycle entry

Summary

Introduction

Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and 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 metabolically distinct subtypes of AML can be identified by high expression of PDK1, associated with low OXPHOS and an increase in stemness transcriptional signatures Insight into such differences will further aid our molecular and cell biological understanding of clonal heterogeneity in AML and will provide means for personalized and subclone-specific targeting strategies

Methods

Results

Conclusion