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Type of publication: Journal Article
Type of document: Full Paper

Year: 2022

Authors: Woess, K; Macho-Maschler, S; Van Ingen Schenau, DS; Butler, M; Lassnig, C; Valcanover, D; Poelzl, A; Meissl, K; Maurer, B; Brandstoetter, T; Vogl, C; Koren, A; Kubicek, S; Orlova, A; Moriggl, R; Strobl, B; Sexl, V; Van Leeuwen, FN; Kuiper, RP; Mueller, M

Title: Oncogenic TYK2P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade.

Source: Haematologica. 2022;



Authors Vetmeduni Vienna:

Brandstötter Tania
Lassnig Caroline
Macho-Maschler Sabine
Maurer Barbara
Meißl Katrin
Moriggl Richard
Müller Mathias
Orlova Anna
Pölzl Andrea
Sexl Veronika
Strobl Birgit
Vogl Claus
Wöss Katharina

Vetmed Research Units
Institute of Pharmacology and Toxicology
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics
Institute of Animal Breeding and Genetics, Unit of Molecular Genetics
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology, Pathophysiology, and Experimental Endocrinology


Abstract:
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-ALLs) or precursor B-ALLs. 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 TYK2P760L in hematopoietic cell systems including primary bone marrow cells. In vivo engraftment of TYK2P760L-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 TYK2P760Ltransformed cell models and ex vivo cultured TYK2P760L-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.


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