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Inhibition of the Atypical Kinase WNK1 as a Therapeutic Strategy in T-cell Acute Lymphoblastic Leukemia

ABSTRACT: Driver mutations in T-cell acute leukemia (T-ALL) rarely affect druggable kinases. However, these kinases can be aberrantly activated or repressed as secondary oncogenic events. Thus, integrating unbiased phosphoproteomics with genomic approaches may offer novel opportunities for target discovery and therapeutic interventions. In our study, we have identified WNK1 as a potential target in T-ALL by pairing a list of vulnerable kinases in T-ALL through a phosphoproteomic screen of 11 T-ALL cell lines. We subsequently validated WNK1 by loss-of-function-based studies and tested WNK chemical inhibitors in several in vitro and in vivo T-ALL models and clinical T-ALL samples. Mechanistically, we showed that WNK1 repression promotes polyploidy, resulting in cell cycle arrest and inhibition of cell proliferation, leading to morphometric changes, such as incomplete cell division or chromosome segregation through altered mitotic spindles assembly and abscission defects. Furthermore, we found that WNK1 is overexpressed in the TAL1/2-related subgroup, not so in normal thymus or lymph nodes, suggesting a potential translational area for clinical exploitation in poor-prognosis T-ALL carrying PTEN mutations and del(6q) aberrancies. Our work also acknowledges a significant contribution of WNK1 kinase in the progression of T-ALL leukemia. Given the lack of sequence similarity in the ATP binding domain compared to other kinases, targeting WNK1 offers a therapeutic window for developing selective probes for this atypical kinase pocket and expands the therapeutic scenario for T-ALL

ORGANISM(S): Homo sapiens

PROVIDER: GSE297311 | GEO | 2026/09/23

REPOSITORIES: GEO

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

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2022-03-07 | PXD031606 | Pride

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