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.

We analyzed public databases and primary patient samples for WNK family expression. CRISPR dependency scores were used to assess gene essentiality. The effects of pharmacological WNK1 inhibition (using WNK463 and WNK11) were evaluated on AML cell lines, primary blasts, and mouse xenograft models. Apoptosis was assessed via pro-apoptotic protein expression (Bim, Puma). Transcriptomic analysis identified downstream pathways, and combination studies with venetoclax were performed in vitro.

WNK1, but not other WNK family members, was highly expressed in AML, particularly in adverse subtypes such as FLT3-ITD mutated AML. CRISPR screening confirmed WNK1 as essential for AML cell survival. Pharmacological inhibition of WNK1 suppressed proliferation of AML cells and primary blasts, induced apoptosis through upregulation of Bim and Puma, and impeded tumor growth in xenograft models without significant toxicity. Transcriptomic analysis revealed that WNK1 inhibition downregulated DNA replication pathway genes (MCM5, CHAF1B, GINS2), whose high expression correlates with poor prognosis. Elevated WNK1 expression was associated with resistance to venetoclax. Combining WNK463 with venetoclax produced synergistic anti-leukemic effects in vitro, accompanied by enhanced Bim upregulation.

This study identifies WNK1 as a key oncogenic driver in AML and establishes WNK1 inhibition as a promising therapeutic strategy that not only suppresses AML progression but also sensitizes leukemia cells to venetoclax. These findings provide a rationale for novel combination regimens to overcome drug resistance in AML.