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

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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Publication Details

Journal
Nature Communications
Published
2025-05-27
DOI
https://doi.org/10.1038/s41467-025-59969-8
Citations
2
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
3.54

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article

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

Pavel V. Shliaha, George Poulogiannis, Kristian Helin, Koutarou Nishimura et al.
2 citations
Nature Communications
Acute Myeloid Leukemia Research
3.54
article

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

Pavel V. Shliaha, George Poulogiannis, Kristian Helin, Koutarou Nishimura, Paolo Gallipoli, Manas Kohli, Roisin B. Reilly, Shunlei Duan, Karl Agger, Aaron R. Van Dyke, Ákos Pál, Florence I. Raynaud, Helene Damhofer, Robert Köchl, Victor L. J. Tybulewicz, Yasmin J. Asad, Max E. Douglas, Jan‐Erik Messling, Xuerui Han, Isabel Peña‐Rømer, Ronald C. Hendrickson
article en
2 citations

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.

Nature CommunicationsVol. 16(1)
University of Copenhagen (DK), Fairfield University (US), Memorial Sloan Kettering Cancer Center (US), Institute of Cancer Research (GB), Queen Mary University of London (GB), The Francis Crick Institute (GB)
Kræftens Bekæmpelse, Cancer Research UK, Institute of Cancer Research, Novo Nordisk, Novo Nordisk Fonden
Responsible consumption and production
Openalex Percentile: Top 8%
Acute Myeloid Leukemia Research
3.54
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