2. Academic Validation
  3. Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma

Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma

  • Leukemia. 2019 Mar;33(3):696-709. doi: 10.1038/s41375-018-0239-1.
Nicole Prutsch 1 2 3,  Elisabeth Gurnhofer 1,  Tobias Suske 1,  Huan Chang Liang 1,  Michaela Schlederer 1,  Simone Roos 3,  Lawren C Wu 4,  Ingrid Simonitsch-Klupp 5,  Andrea Alvarez-Hernandez 5,  Christoph Kornauth 5,  Dario A Leone 1,  Jasmin Svinka 6,  Robert Eferl 6,  Tanja Limberger 1,  Astrid Aufinger 1,  Nitesh Shirsath 7,  Peter Wolf 7,  Thomas Hielscher 8,  Christina Sternberg 3 9 10,  Fritz Aberger 9,  Johannes Schmoellerl 11,  Dagmar Stoiber 11 12,  Birgit Strobl 13,  Ulrich Jäger 14,  Philipp B Staber 14,  Florian Grebien 11,  Richard Moriggl 11 13 15,  Mathias Müller 13,  Giorgio G Inghirami 16 17,  Takaomi Sanda 18,  A Thomas Look 2,  Suzanne D Turner 17 19,  Lukas Kenner # 20 21 22 23 24,  Olaf Merkel # 25 26
Affiliations

Affiliations

  • 1 Clinical Institute of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria.
  • 2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
  • 3 Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.
  • 4 Department of Oncology, Amgen Discovery Research, South San Francisco, CA, 94080, USA.
  • 5 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
  • 6 Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.
  • 7 Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.
  • 8 Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 9 Department of Molecular Biology, Cancer Cluster Salzburg, Faculty of Natural Sciences, Paris Lodron University, Salzburg, Austria.
  • 10 Department of Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
  • 11 Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
  • 12 Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 13 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
  • 14 Department of Medicine I, Clinical Division of Hematology and Hemostaseology and Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.
  • 15 Medical University of Vienna, Vienna, Austria.
  • 16 Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NYC, USA.
  • 17 European Research Initiative for ALK related malignancies (www.erialcl.net), Vienna, Austria.
  • 18 Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore.
  • 19 Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK.
  • 20 Clinical Institute of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria. lukas.kenner@medunwien.ac.at.
  • 21 Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria. lukas.kenner@medunwien.ac.at.
  • 22 Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria. lukas.kenner@medunwien.ac.at.
  • 23 European Research Initiative for ALK related malignancies (www.erialcl.net), Vienna, Austria. lukas.kenner@medunwien.ac.at.
  • 24 CBMed Core Lab2, Medical University of Vienna, Vienna, Austria. lukas.kenner@medunwien.ac.at.
  • 25 Clinical Institute of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria. olaf.merkel@meduniwien.ac.at.
  • 26 European Research Initiative for ALK related malignancies (www.erialcl.net), Vienna, Austria. olaf.merkel@meduniwien.ac.at.
  • # Contributed equally.
PMID: 30131584 DOI: 10.1038/s41375-018-0239-1
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.

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