{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T23:45:13Z","timestamp":1789083913764,"version":"build-2803163510"},"reference-count":81,"publisher":"American Society of Hematology","issue":"11","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,10]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Driver mutations in T-cell acute lymphoblastic 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 identified WNK1 (with no lysine [K]) as a potential target in T-ALL by pairing a list of vulnerable kinases with data from a phosphoproteomic screen of T-ALL cell lines. We subsequently validated WNK1 by loss-of-function\u2013based studies and tested WNK inhibitors in several in vitro and in vivo T-ALL models and clinical T-ALL samples. We showed that therapeutic WNK1 repression promotes polyploidy, resulting in cell proliferation arrest, and morphometric changes, such as incomplete cell division or chromosome segregation through altered mitotic spindle assembly and abscission defects. Furthermore, we found that WNK1 is overexpressed in the TAL1\/2-related subgroup, but not 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). Our work also reports a functional contribution of WNK1 in the leukemia establishment and progression. Structurally WNK1 is an atypical serine\/threonine kinase that diverges from canonical kinases by lacking the conserved lysine in subdomain II, instead featuring a cysteine in subdomain I, which is critical for adenosine triphosphate (ATP) binding. This unusual structural configuration creates a distinct ATP-binding pocket with limited sequence similarity to conventional kinases, offering a unique opportunity to develop highly selective small molecules. Targeting this atypical ATP domain could thus provide a therapeutic advantage and broaden the treatment landscape for T-ALL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025029901","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:36:37Z","timestamp":1779212197000},"page":"1423-1439","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of the atypical kinase WNK1 as a therapeutic strategy in TAL-related T-cell acute lymphoblastic leukemia"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5229-5395","authenticated-orcid":false,"given":"Anna","family":"Montanaro","sequence":"first","affiliation":[{"name":"1Department of Medicine and Surgery, University of Parma, Parma, Italy"},{"name":"2Translational Hematology and Chemogenomics Laboratory, University of Parma, Parma, 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