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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2019

AutorInnen: Prutsch, N; Gurnhofer, E; Suske, T; Liang, HC; Schlederer, M; Roos, S; Wu, LC; Simonitsch-Klupp, I; Alvarez-Hernandez, A; Kornauth, C; Leone, DA; Svinka, J; Eferl, R; Limberger, T; Aufinger, A; Shirsath, N; Wolf, P; Hielscher, T; Sternberg, C; Aberger, F; Schmoellerl, J; Stoiber, D; Strobl, B; Jäger, U; Staber, PB; Grebien, F; Moriggl, R; Müller, M; Inghirami, GG; Sanda, T; Look, AT; Turner, SD; Kenner, L; Merkel, O

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

Quelle: Leukemia. 2019; 33(3):696-709



Autor/innen der Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Müller Mathias
Prutsch Nicole
Strobl Birgit
Tangermann Simone

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik, Abteilung für Funktionelle Krebsgenomik
Institut für Pathologie, Abteilung für Labortierpathologie
Institut für Tierzucht und Genetik, Abteilung für Molekulare Genetik


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.

Keywords Pubmed: Anaplastic Lymphoma Kinasegenetics
Animals
Apoptosisdrug effectsgenetics
Cell Line, Tumor
Cell Survivaldrug effectsgenetics
Gene Expression Regulation, Neoplasticdrug effectsgenetics
Humans
Lymphoma, Large-Cell, Anaplasticdrug therapygenetics
Mice
Myeloid Cell Leukemia Sequence 1 Proteingenetics
Phosphorylationdrug effectsgenetics
Protein Kinase Inhibitorspharmacology
Protein-Tyrosine Kinasesgenetics
STAT1 Transcription Factorgenetics
STAT3 Transcription Factorgenetics
Signal Transductiondrug effectsgenetics
TYK2 Kinasegenetics
Translocation, Geneticdrug effectsgenetics

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