Journal
LEUKEMIA
Volume 33, Issue 3, Pages 696-709Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-018-0239-1
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Funding
- European Union's Horizon 2020 Marie Sklodowska Curie Innovative Training Network ALKATRAS [675712]
- Jubilaumsfond der Osterreichischen Nationalbank [14856]
- FWF grants [P26011, P29251]
- BM Fonds [15142]
- Margaretha Hehberger Stiftung [15142]
- AIRC 5 x 1000 [10007]
- Leukemia Lymphoma Society (SCOR 2015)
- Austrian Science Fund FWF [W1241]
- Medical University of Graz through the PhD program Molecular Fundamentals of Inflammation (DK-MOLIN)
- FWF [SFB F6105, F6106, F6101]
- [SFB F4707]
- Austrian Science Fund (FWF) [P26011, P25629, P27132, P29251, W1241, W1213] Funding Source: Austrian Science Fund (FWF)
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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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