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.

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.

MeSH terms

  • Amino Acids* / metabolism
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Mechanistic Target of Rapamycin Complex 1* / genetics
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Mice
  • Phosphorylation
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction
  • WNK Lysine-Deficient Protein Kinase 1* / genetics
  • WNK Lysine-Deficient Protein Kinase 1* / metabolism

Substances

  • Mechanistic Target of Rapamycin Complex 1
  • WNK Lysine-Deficient Protein Kinase 1
  • Amino Acids
  • WNK1 protein, human
  • Protein Serine-Threonine Kinases
  • STK39 protein, human