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

Nicole Prutsch,Christina Sternberg,Ulrich Jäger,Mathias Müller,Suzanne Turner ,Takaomi Sanda,A Thomas Look ,Florian Grebien,Dario A Leone ,Giorgio Inghirami ,Nitesh Shirsath,Robert Eferl,Fritz Aberger,Thomas Hielscher,Richard Moriggl,Tanja Limberger,Johannes Schmoellerl,Simone Roos,Astrid Aufinger,Andrea Alvarez-Hernandez,Michaela Schlederer,Peter Wolf,Jasmin Svinka,Huan-Chang Liang ,Lawren C Wu ,Birgit Strobl,Dagmar Stoiber,Lukas Kenner,Christoph Kornauth,Elisabeth Gurnhofer,Ingrid Simonitsch‐Klupp ,Tobias Suske,Philipp B Staber ,Olaf Merkel

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.

Highlights

TYK2 was the first Janus kinase described, and it was shown to collaborate with JAK1 to facilitate interferon-α/β (IFN) responsiveness [1, 2]
We show here that TYK2 is expressed at high levels in human anaplastic large cell lymphoma (ALCL) cell lines and primary ALCL patient samples
T-cell-specific loss of TYK2 in a transgenic mouse model of NPM-anaplastic lymphoma kinase (ALK) driven lymphoma resulted in delayed tumor growth and significantly prolonged overall survival of the mice. siRNA-mediated TYK2 depletion as well as CRISPR/ Cas9-mediated TYK2 disruption led to rapid induction of cell death in ALCL cells

Summary

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TYK2 was the first Janus kinase described, and it was shown to collaborate with JAK1 to facilitate interferon-α/β (IFN) responsiveness [1, 2]. Somatic TYK2 fusion proteins have been detected in ALL [8], AML [9], cutaneous [5], and systemic ALCLs that lack anaplastic lymphoma kinase (ALK) fusion genes [6]. We show here that the TYK2 tyrosine kinase is expressed in human ALCLs irrespective of ALK status and is essential for tumor cell viability. Genetic studies in a transgenic NPM-ALK driven lymphoma model demonstrate that T cell-specific loss of Tyk delays the onset of tumors and prolongs the survival of mice. For detection of downstream targets, ALCL cells were incubated with TYK2 inhibitors or pan-JAK inhibitors (including 1 μM JAK inhibitor I, Calbiochem, San Diego, CA, USA) for 3 or 6 h and incubated with IFN-α for 10 min before immunoblot analysis. Western blot quantification was conducted using Image J version 2007

Results

Discussion

Compliance with ethical standards