WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain AML growth

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 leukemic cells in vitro and in vivo. Furthermore, we show that the WNK1-OXSR1/STK39 pathway controls mTOR signalling via regulating amino acid uptake through a mechanism involving the phosphorylation of amino acid transporters, such as SLC38A2. Our results demonstrate a critical role of the WNK1-OXSR1/STK39 pathway in regulating amino acid uptake and in AML maintenance. Moreover, our mode of action studies suggests that WNK1 and OXSR1/STK39 inhibitors could be effective in a broad range of cancer types.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Pavel Shliaha  

LAB HEAD: Ronald Hendrickson

PROVIDER: PXD041902 | Pride | 2025-06-02

REPOSITORIES: Pride