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

  • Nat Commun. 2025 May 27;16(1):4920. doi: 10.1038/s41467-025-59969-8.
Shunlei Duan  #  1  2 ,  Karl Agger  #  2 ,  Jan-Erik Messling  2 ,  Koutarou Nishimura  2  3 ,  Xuerui Han  1  2 ,  Isabel Peña-Rømer  1 ,  Pavel Shliaha  4 ,  Helene Damhofer  1  2  3 ,  Max Douglas  1 ,  Manas Kohli  1 ,  Akos Pal  5 ,  Yasmin Asad  5 ,  Aaron Van Dyke  6 ,  Raquel Reilly  6 ,  Robert Köchl  7 ,  Victor L J Tybulewicz  7 ,  Ronald C Hendrickson  4 ,  Florence I Raynaud  5 ,  Paolo Gallipoli  8 ,  George Poulogiannis  1 ,  Kristian Helin  9  10  11
Affiliations
  • 1. Division of Cell and Molecular Biology, The Institute of Cancer Research, Londo, UK.
  • 2. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • 3. Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4. Microchemistry and Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5. Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
  • 6. Department of Chemistry & Biochemistry, Fairfield University, Fairfield, CT, USA.
  • 7. The Francis Crick Institute, London, UK.
  • 8. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 9. Division of Cell and Molecular Biology, The Institute of Cancer Research, Londo, UK. [email protected].
  • 10. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark. [email protected].
  • 11. Cell Biology Program and Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 40425534 DOI: 10.1038/s41467-025-59969-8
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.

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