WNK1 signalling regulates amino acid transport and mTORC1 activity to sustain acute myeloid leukaemia growth
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.
Article Details
Authors (21)
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 Van Dyke
Raquel Reilly
Robert Köchl
Victor L. J. Tybulewicz
The Francis Crick Institute, London, UK.
Ronald C. Hendrickson
Florence I. Raynaud
Paolo Gallipoli
George Poulogiannis
Kristian Helin