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WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth

Author

Listed:
  • Shunlei Duan

    (The Institute of Cancer Research
    University of Copenhagen)

  • Karl Agger

    (University of Copenhagen)

  • Jan-Erik Messling

    (University of Copenhagen)

  • Koutarou Nishimura

    (University of Copenhagen
    Memorial Sloan Kettering Cancer Center)

  • Xuerui Han

    (The Institute of Cancer Research
    University of Copenhagen)

  • Isabel Peña-Rømer

    (The Institute of Cancer Research)

  • Pavel Shliaha

    (Memorial Sloan Kettering Cancer Center)

  • Helene Damhofer

    (The Institute of Cancer Research
    University of Copenhagen
    Memorial Sloan Kettering Cancer Center)

  • Max Douglas

    (The Institute of Cancer Research)

  • Manas Kohli

    (The Institute of Cancer Research)

  • Akos Pal

    (The Institute of Cancer Research)

  • Yasmin Asad

    (The Institute of Cancer Research)

  • Aaron Dyke

    (Fairfield University)

  • Raquel Reilly

    (Fairfield University)

  • Robert Köchl

    (The Francis Crick Institute)

  • Victor L. J. Tybulewicz

    (The Francis Crick Institute)

  • Ronald C. Hendrickson

    (Memorial Sloan Kettering Cancer Center)

  • Florence I. Raynaud

    (The Institute of Cancer Research)

  • Paolo Gallipoli

    (Queen Mary University of London)

  • George Poulogiannis

    (The Institute of Cancer Research)

  • Kristian Helin

    (The Institute of Cancer Research
    University of Copenhagen
    Memorial Sloan Kettering Cancer Center)

Abstract

The lack of curative therapies for acute myeloid leukaemia (AML) remains an ongoing challenge despite recent advances in the understanding of the molecular basis of the disease. Here we identify the WNK1-OXSR1/STK39 pathway as a previously uncharacterised dependency in AML. We show that genetic depletion and pharmacological inhibition of WNK1 or its downstream phosphorylation targets OXSR1 and STK39 strongly reduce cell proliferation and induce apoptosis in leukaemia cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTORC1 signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our findings underscore an important role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and driving AML progression.

Suggested Citation

  • Shunlei Duan & Karl Agger & Jan-Erik Messling & Koutarou Nishimura & Xuerui Han & Isabel Peña-Rømer & Pavel Shliaha & Helene Damhofer & Max Douglas & Manas Kohli & Akos Pal & Yasmin Asad & Aaron Dyke , 2025. "WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59969-8
    DOI: 10.1038/s41467-025-59969-8
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    References listed on IDEAS

    as
    1. Iris Müller & Ann Sophie Moroni & Daria Shlyueva & Sudeep Sahadevan & Erwin M. Schoof & Aliaksandra Radzisheuskaya & Jonas W. Højfeldt & Tülin Tatar & Richard P. Koche & Chang Huang & Kristian Helin, 2021. "MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Robert A. J. Signer & Jeffrey A. Magee & Adrian Salic & Sean J. Morrison, 2014. "Haematopoietic stem cells require a highly regulated protein synthesis rate," Nature, Nature, vol. 509(7498), pages 49-54, May.
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