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

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.