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

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, Raquel Reilly, Robert Köchl, Victor L. J. Tybulewicz, Ronald C. Hendrickson, Florence I. Raynaud, Paolo Gallipoli, George Poulogiannis and Kristian Helin ()
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Shunlei Duan: The Institute of Cancer Research
Karl Agger: University of Copenhagen
Jan-Erik Messling: University of Copenhagen
Koutarou Nishimura: University of Copenhagen
Xuerui Han: The Institute of Cancer Research
Isabel Peña-Rømer: The Institute of Cancer Research
Pavel Shliaha: Memorial Sloan Kettering Cancer Center
Helene Damhofer: The Institute of Cancer Research
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

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59969-8

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