Inhibition of the Atypical Kinase WNK1 as a Therapeutic Strategy in TAL-related 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 identified WNK1 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-based 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 diverge from canonical kinases by lacking the conserved lysine in subdomain II, instead featuring a cysteine in subdomain I, which is critical for 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.
Article Details
Authors (26)
Anna Montanaro
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Italy
Gregorio Monica
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Italy
Raffaella Zamponi
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Italy
Anna D'Antuono
Department of Medicine and Surgery, University of Parma, Italy, Parma, Italy
Alice Andreani
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Parma, Italy
Pietro Andrei
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Parma, Italy
Angela Su
School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States
Alessia Ciringione
University of Parma, Italy, Parma, Italy
Gabriella Sammarelli
Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Italy, Parma, Italy
Giannalisa Todaro
Hematology and BMT Unit, Azienda Ospedaliero-Universitaria di Parma, Italy, Parma, Italy
Roberto Rosati
Roberta La Starza
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Cristina Mecucci
2Laboratory of Molecular Medicine, Centro di Ricerca Emato-Oncologico, Santa Maria della Misericordia Hospital and Department of Medicine and Surgery, University of Perugia, Perugia, Italy
Loredana Elia
ematologia, Roma, Italy
Andrea Gherli
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Italy
Federica Vento
4Department of Medicine and Surgery, Translational Hematology and Chemogenomics, University of Parma, Parma, Italy
Elisa Simoncini
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Italy
Bruno Lorusso
Department of Medicine and Surgery, University of Parma, Italy, Parma, Italy
Costanza Anna Maria Lagastra
Department of Medicine and Surgery, University of Parma, Italy, Parma, Italy
Mariateresa Giaimo
Translational Hematology and Chemogenomics Laboratory, University of Parma, Italy, Italy
Luca Pagliaro
4Department of Medicine and Surgery, Translational Hematology and Chemogenomics, University of Parma, Parma, Italy
Matteo Marchesini
Connie R Jimenez
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, The Netherlands, Netherlands
Federico Quaini
University of Parma, Parma, PA, Italy
Kimberly Stegmaier
Department of Pediatric Oncology, Dana-Farber Cancer Institute
Giovanni Roti
University of Parma, Parma, Italy