Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma
| Autor: | 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 |
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| Přispěvatelé: | Aberger, Fritz [0000-0003-2009-6305], Grebien, Florian [0000-0003-4289-2281], Moriggl, Richard [0000-0003-0918-9463], Sanda, Takaomi [0000-0003-1621-4954], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | Leukemia |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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