Woess, Katharina (University of Veterinary Medicine Vienna) Katharina Woess Mueller, Mathias (University of Veterinary Medicine Vienna) Mathias Mueller Vogl, Claus (University of Veterinary Medicine Vienna) Claus Vogl Brandstoetter, Tania (University of Veterinary Medicine Vienna) Tania Brandstoetter Maurer, Barbara (University of Veterinary Medicine Vienna) Barbara Maurer Macho-Maschler, Sabine (University of Veterinary Medicine Vienna) Sabine Macho-Maschler Van Ingen Schenau, Dorette S. (Princess Máxima Center for Pediatric Oncology) Dorette S. Van Ingen Schenau Butler, Miriam (Princess Máxima Center for Pediatric Oncology) Miriam Butler Lassnig, Caroline (University of Veterinary Medicine Vienna) Caroline Lassnig Valcanover, Daniel (University of Veterinary Medicine Vienna) Daniel Valcanover Poelzl, Andrea (University of Veterinary Medicine Vienna) Andrea Poelzl Meissl, Katrin (University of Veterinary Medicine Vienna) Katrin Meissl Kuiper, Roland P. (Princess Máxima Center for Pediatric Oncology / University Medical Center Utrecht) Roland P. Kuiper Van Leeuwen, Frank N. (Princess Máxima Center for Pediatric Oncology) Frank N. Van Leeuwen Sexl, Veronika (University of Veterinary Medicine Vienna) Veronika Sexl Strobl, Birgit (University of Veterinary Medicine Vienna) Birgit Strobl Moriggl, Richard (University of Veterinary Medicine Vienna) Richard Moriggl Orlova, Anna (University of Veterinary Medicine Vienna) Anna Orlova Kubicek, Stefan (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences) Stefan Kubicek Koren, Anna (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences) Anna Koren Ferrata Storti Foundation 2023 Tyrosine kinase 2 (TYK2) is a member of the Janus kinase/signal transducer and activator of transcription pathway, which is central in cytokine signaling. Previously, germline TYK2 mutations have been described in two patients developing de novo T-cell acute lymphoblastic leukemias (T-ALL) or precursor B-ALL. The mutations (P760L and G761V) are located within the regulatory pseudokinase domain and lead to constitutive activation of TYK2. We demonstrate the transformation capacity of TYK2 P760L in hematopoietic cell systems including primary bone marrow cells. In vivo engraftment of TYK2 P760L-expressing cell lines led to development of leukemia. A kinase inhibitor screen uncovered that oncogenic TYK2 acts synergistically with the PI3K/AKT/mTOR and CDK4/6 pathways. Accordingly, the TYK2-specific inhibitor deucravacitinib (BMS986165) reduces cell viability of TYK2 P760L-transformed cell models and ex vivo cultured TYK2 P760L-mutated patient- derived xenograft cells most efficiently when combined with mTOR or CDK4/6 inhibitors. Our study thereby pioneers novel treatment options for patients suffering from TYK2-driven acute leukemia. PDFDocument en 2023-10-25T12:47:58.559Z Acute Lymphoblastic-Leukemia; Jak-Stat Pathway; Cell-Cycle; Preclinical Characterization; Selective Inhibitor; Activation; Cancer; Mutations; Jak/Stat; Lesions 2941299 b application/pdf CC BY-NC 4.0 International