IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-28737-3.html
   My bibliography  Save this article

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

Author

Listed:
  • Ayşegül Erdem

    (University Medical Center Groningen, University of Groningen
    Department of Biochemistry and Molecular Biology, Faculty of Biology)

  • Silvia Marin

    (Department of Biochemistry and Molecular Biology, Faculty of Biology
    CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III
    Institute of Biomedicine of University of Barcelona)

  • Diego A. Pereira-Martins

    (University Medical Center Groningen, University of Groningen
    University of São Paulo)

  • 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
    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
    CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III
    Institute of Biomedicine of University of Barcelona)

  • Jan Jacob Schuringa

    (University Medical Center Groningen, University of Groningen)

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.

Suggested Citation

  • 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. Bro, 2022. "The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28737-3
    DOI: 10.1038/s41467-022-28737-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-28737-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-28737-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kristina Anderson & Christoph Lutz & Frederik W. van Delft & Caroline M. Bateman & Yanping Guo & Susan M. Colman & Helena Kempski & Anthony V. Moorman & Ian Titley & John Swansbury & Lyndal Kearney & , 2011. "Genetic variegation of clonal architecture and propagating cells in leukaemia," Nature, Nature, vol. 469(7330), pages 356-361, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yi-Ing Chen & Chin-Chun Chang & Min-Fen Hsu & Yung-Ming Jeng & Yu-Wen Tien & Ming-Chu Chang & Yu-Ting Chang & Chun-Mei Hu & Wen-Hwa Lee, 2022. "Homophilic ATP1A1 binding induces activin A secretion to promote EMT of tumor cells and myofibroblast activation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Wenxue Ma & Alejandro Gutierrez & Daniel J Goff & Ifat Geron & Anil Sadarangani & Christina A M Jamieson & Angela C Court & Alice Y Shih & Qingfei Jiang & Christina C Wu & Kang Li & Kristen M Smith & , 2012. "NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches," PLOS ONE, Public Library of Science, vol. 7(6), pages 1-14, June.
    3. Hao Wang & R. Alejandro Sica & Gurbakhash Kaur & Phillip M. Galbo & Zhixin Jing & Christopher D. Nishimura & Xiaoxin Ren & Ankit Tanwar & Bijan Etemad-Gilbertson & Britta Will & Deyou Zheng & David Fo, 2024. "TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Naomi Kawashima & Yuichi Ishikawa & Jeong Hui Kim & Yoko Ushijima & Akimi Akashi & Yohei Yamaguchi & Hikaru Hattori & Marie Nakashima & Seara Ikeno & Rika Kihara & Takahiro Nishiyama & Takanobu Morish, 2022. "Comparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Yuxuan Liu & Zhimin Gu & Hui Cao & Pranita Kaphle & Junhua Lyu & Yuannyu Zhang & Wenhuo Hu & Stephen S. Chung & Kathryn E. Dickerson & Jian Xu, 2021. "Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28737-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.