1. Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma
- Author
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Thomas Hielscher, Fritz Aberger, Florian Grebien, Takaomi Sanda, Elisabeth Gurnhofer, Tanja Limberger, Jasmin Svinka, Christoph Kornauth, Suzanne D. Turner, Peter Wolf, Astrid Aufinger, Andrea Alvarez-Hernandez, Johannes Schmoellerl, Simone Roos, Mathias Müller, Lukas Kenner, Philipp B. Staber, Ingrid Simonitsch-Klupp, Richard Moriggl, Robert Eferl, Giorgio Inghirami, Nicole Prutsch, Nitesh Shirsath, Lawren C. Wu, Tobias Suske, Dagmar Stoiber, Dario A. Leone, Michaela Schlederer, A. Thomas Look, Birgit Strobl, Olaf Merkel, Ulrich Jäger, Huan Chang Liang, Aberger, Fritz [0000-0003-2009-6305], Grebien, Florian [0000-0003-4289-2281], Moriggl, Richard [0000-0003-0918-9463], Sanda, Takaomi [0000-0003-1621-4954], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,Cancer Research ,Cell Survival ,Apoptosis ,Article ,Translocation, Genetic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Targeted therapies ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Anaplastic lymphoma kinase ,T-cell lymphoma ,Animals ,Humans ,Anaplastic Lymphoma Kinase ,Phosphorylation ,Autocrine signalling ,Anaplastic large-cell lymphoma ,Protein Kinase Inhibitors ,TYK2 Kinase ,Chemistry ,Large cell ,Correction ,Hematology ,Protein-Tyrosine Kinases ,medicine.disease ,Lymphoma ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,STAT1 Transcription Factor ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Lymphoma, Large-Cell, Anaplastic ,Myeloid Cell Leukemia Sequence 1 Protein ,Signal transduction ,Tyrosine kinase ,Signal Transduction - Abstract
TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1, a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL.
- Published
- 2019