phaidra.vetmeduni.ac.at o:2234 DOI 10.3324/haematol.2021.279848 Oncogenic TYK2P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade 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. eng Acute Lymphoblastic-Leukemia; Jak-Stat Pathway; Cell-Cycle; Preclinical Characterization; Selective Inhibitor; Activation; Cancer; Mutations; Jak/Stat; Lesions 2024-10-29T13:29:20.383Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Woess;Katharina; FN:Katharina Woess END:VCARD BEGIN:VCARD VERSION:3.0 N:Mueller;Mathias; FN:Mathias Mueller X-ORCID:https://orcid.org/0000-0002-7879-3552 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kuiper;Roland P.; FN:Roland P. Kuiper END:VCARD BEGIN:VCARD VERSION:3.0 N:Van Leeuwen;Frank N.; FN:Frank N. Van Leeuwen END:VCARD BEGIN:VCARD VERSION:3.0 N:Sexl;Veronika; FN:Veronika Sexl X-ORCID:https://orcid.org/0000-0001-9363-0412 END:VCARD BEGIN:VCARD VERSION:3.0 N:Strobl;Birgit; FN:Birgit Strobl X-ORCID:https://orcid.org/0000-0001-5716-3212 END:VCARD BEGIN:VCARD VERSION:3.0 N:Moriggl;Richard; FN:Richard Moriggl X-ORCID:https://orcid.org/0000-0003-0918-9463 END:VCARD BEGIN:VCARD VERSION:3.0 N:Orlova;Anna; FN:Anna Orlova X-ORCID:https://orcid.org/0000-0001-9262-7529 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kubicek;Stefan; FN:Stefan Kubicek END:VCARD BEGIN:VCARD VERSION:3.0 N:Koren;Anna; FN:Anna Koren END:VCARD BEGIN:VCARD VERSION:3.0 N:Vogl;Claus; FN:Claus Vogl X-ORCID:https://orcid.org/0000-0002-3996-7863 END:VCARD BEGIN:VCARD VERSION:3.0 N:Brandstoetter;Tania; FN:Tania Brandstoetter X-ORCID:https://orcid.org/0000-0003-4037-5352 END:VCARD BEGIN:VCARD VERSION:3.0 N:Maurer;Barbara; FN:Barbara Maurer X-ORCID:https://orcid.org/0000-0003-1343-8194 END:VCARD BEGIN:VCARD VERSION:3.0 N:Macho-Maschler;Sabine; FN:Sabine Macho-Maschler END:VCARD BEGIN:VCARD VERSION:3.0 N:Van Ingen Schenau;Dorette S.; FN:Dorette S. Van Ingen Schenau END:VCARD BEGIN:VCARD VERSION:3.0 N:Butler;Miriam; FN:Miriam Butler END:VCARD BEGIN:VCARD VERSION:3.0 N:Lassnig;Caroline; FN:Caroline Lassnig X-ORCID:https://orcid.org/0000-0001-7905-3620 END:VCARD BEGIN:VCARD VERSION:3.0 N:Valcanover;Daniel; FN:Daniel Valcanover END:VCARD BEGIN:VCARD VERSION:3.0 N:Poelzl;Andrea; FN:Andrea Poelzl X-ORCID:https://orcid.org/0000-0002-4005-7728 END:VCARD BEGIN:VCARD VERSION:3.0 N:Meissl;Katrin; FN:Katrin Meissl END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by-nc/4.0 application/pdf 2941299 https://phaidra.vetmeduni.ac.at/o:2234 https://phaidra.vetmeduni.ac.at/api/object/o:2234/thumbnail LOMv1.0 discipline