Targeting WNK1 suppresses acute myeloid leukemia progression and enhances sensitivity to venetoclax

Here, we demonstrate that WNK1 is a novel therapeutic target in AML. Analysis of public databases and primary patient samples reveals that WNK1, but not other WNK family members, is highly expressed in AML, particularly in adverse subtypes such as FLT3-ITD mutated AML.

CRISPR dependency scores confirm WNK1 is essential for AML cell survival. Pharmacological inhibition of WNK1 using WNK463 or WNK11 significantly suppresses the proliferation of AML cell lines and primary blasts, induces apoptosis through upregulation of pro-apoptotic proteins Bim and Puma, and impedes tumor growth in mouse xenograft models without significant toxicity. Transcriptomic analysis indicates that WNK1 inhibition downregulates genes involved in DNA replication pathways, including MCM5, CHAF1B, and GINS2, whose high expression correlates with poor prognosis.