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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Acknowledgements

S.D.T., L.K., and O.M. receive funding from the European Union’s Horizon 2020 Marie Sklodowska Curie Innovative Training Network ALKATRAS under grant agreement 675712, and H.C.L. is a Marie Curie Early Stage Researcher within this program. S.D.T. is a Bloodwise fellow. This work was supported by the “Jubiläumsfond der Österreichischen Nationalbank” (grant No. 14856 to O.M.), L.K. was supported by FWF grants P26011 and P29251. L.K. and O.M. were supported by the BM Fonds No. 15142 and the Margaretha Hehberger Stiftung No. 15142. G.I. was supported by the AIRC 5 × 1000 (No. 10007) and by the Leukemia Lymphoma Society (SCOR 2015). The work of N.S. and P.W. was supported by the Austrian Science Fund FWF (W1241) and the Medical University of Graz through the PhD program Molecular Fundamentals of Inflammation (DK-MOLIN). R.M., M.M., and B.S. were funded by the FWF SFB F6105, F6106, and F6101. R.M. was additionally funded by SFB F4707.

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Author notes

  1. These authors contributed equally: Lukas Kenner, Olaf Merkel

Affiliations

  1. Clinical Institute of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria

    • Nicole Prutsch
    • , Elisabeth Gurnhofer
    • , Tobias Suske
    • , Huan Chang Liang
    • , Michaela Schlederer
    • , Dario A. Leone
    • , Tanja Limberger
    • , Astrid Aufinger
    • , Lukas Kenner
    •  & Olaf Merkel
  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA

    • Nicole Prutsch
    •  & A. Thomas Look
  3. Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria

    • Nicole Prutsch
    • , Simone Roos
    •  & Lukas Kenner
  4. Department of Oncology, Amgen Discovery Research, South San Francisco, CA, 94080, USA

    • Lawren C. Wu
  5. Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

    • Ingrid Simonitsch-Klupp
    • , Andrea Alvarez-Hernandez
    •  & Christoph Kornauth
  6. Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria

    • Jasmin Svinka
    •  & Robert Eferl
  7. Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria

    • Nitesh Shirsath
    •  & Peter Wolf
  8. Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    • Thomas Hielscher
  9. Department of Molecular Biology, Cancer Cluster Salzburg, Faculty of Natural Sciences, Paris Lodron University, Salzburg, Austria

    • Fritz Aberger
  10. Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria

    • Johannes Schmoellerl
    • , Dagmar Stoiber
    • , Florian Grebien
    • , Richard Moriggl
    •  & Lukas Kenner
  11. Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    • Dagmar Stoiber
  12. Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria

    • Birgit Strobl
    • , Richard Moriggl
    •  & Mathias Müller
  13. Department of Medicine I, Clinical Division of Hematology and Hemostaseology and Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria

    • Ulrich Jäger
    •  & Philipp B. Staber
  14. Medical University of Vienna, Vienna, Austria

    • Richard Moriggl
  15. Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NYC, USA

    • Giorgio G. Inghirami
  16. European Research Initiative for ALK related malignancies (www.erialcl.net), Vienna, Austria

    • Giorgio G. Inghirami
    • , Suzanne D. Turner
    • , Lukas Kenner
    •  & Olaf Merkel
  17. Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore

    • Takaomi Sanda
  18. Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK

    • Suzanne D. Turner
  19. CBMed Core Lab2, Medical University of Vienna, Vienna, Austria

    • Lukas Kenner

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The authors declare that they have no conflict of interest.

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Correspondence to Lukas Kenner or Olaf Merkel.

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https://doi.org/10.1038/s41375-018-0239-1