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

The With-No-Lysine (WNK) kinase family plays critical roles in cellular signaling, yet its significance in acute myeloid leukemia (AML) remains unclear. 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. Importantly, elevated WNK1 expression is associated with resistance to the BCL-2 inhibitor venetoclax, a frontline AML therapy. Combining WNK463 with venetoclax exhibits synergistic anti-leukemic effects in vitro, accompanied by enhanced Bim upregulation. In summary, our study identifies WNK1 as a key oncogenic driver in AML and establishes WNK1 inhibition as a promising therapeutic strategy that suppresses AML progression and sensitizes leukemia cells to venetoclax, providing a rationale for novel combination regimens to overcome drug resistance.