Duan Shunlei, Agger Karl, Messling Jan-Erik, Nishimura Koutarou, Han Xuerui, Peña-Rømer Isabel, Shliaha Pavel, Damhofer Helene, Douglas Max, Kohli Manas, Pal Akos, Asad Yasmin, Van Dyke Aaron, Reilly Raquel, Köchl Robert, Tybulewicz Victor L J, Hendrickson Ronald C, Raynaud Florence I, Gallipoli Paolo, Poulogiannis George, Helin Kristian
Division of Cell and Molecular Biology, The Institute of Cancer Research, Londo, UK.
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
Nat Commun. 2025 May 27;16(1):4920. doi: 10.1038/s41467-025-59969-8.
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.
尽管在对急性髓系白血病（AML）分子基础的理解方面取得了最新进展，但缺乏针对该疾病的治愈性疗法仍然是一个持续存在的挑战。在此，我们确定WNK1 - OXSR1/STK39信号通路是AML中一种先前未被表征的依赖性因素。我们表明，WNK1或其下游磷酸化靶点OXSR1和STK39的基因缺失以及药理学抑制，在体外和体内均能强烈降低白血病细胞的增殖并诱导其凋亡。此外，我们表明WNK1 - OXSR1/STK39信号通路通过一种涉及氨基酸转运体（如SLC38A2）磷酸化的机制来调节氨基酸摄取，从而控制mTORC1信号传导。我们的研究结果强调了WNK1 - OXSR1/STK39信号通路在调节氨基酸摄取和推动AML进展中的重要作用。
