title: TYK2 is a key regulator of the surveillance of B lymphoid tumors.
abstract: Aberrant activation of the JAK-STAT pathway has been implicated in tumor formation; for example, constitutive activation of JAK2 kinase or the enforced expression of STAT5 induces leukemia in mice. We show here that the Janus kinase TYK2 serves an opposite function. Mice deficient in TYK2 developed Abelson-induced B lymphoid leukemia/lymphoma as well as TEL-JAK2-induced T lymphoid leukemia with a higher incidence and shortened latency compared with WT controls. The cell-autonomous properties of Abelson murine leukemia virus-transformed (A-MuLV-transformed) TYK2(-/-) cells were unaltered, but the high susceptibility of TYK2(-/-) mice resulted from an impaired tumor surveillance, and accordingly, TYK2(-/-) A-MuLV-induced lymphomas were easily rejected after transplantation into WT hosts. The increased rate of leukemia/lymphoma formation was linked to a decreased in vitro cytotoxic capacity of TYK2(-/-) NK and NKT cells toward tumor-derived cells. RAG2/TYK2 double-knockout mice succumbed to A-MuLV-induced leukemia/lymphoma faster than RAG2(-/-)TYK2(+/-) mice. This defines NK cells as key players in tumor surveillance in Abelson-induced malignancies. Our observations provide compelling evidence that TYK2 is an important regulator of lymphoid tumor surveillance.
authors.affiliation: Department of Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stoiber
authors.forename: Boris
authors.initials: B
authors.lastname: Kovacic
authors.forename: Christian
authors.initials: C
authors.lastname: Schuster
authors.forename: Carola
authors.initials: C
authors.lastname: Schellack
authors.forename: Marina
authors.initials: M
authors.lastname: Karaghiosoff
authors.forename: Rita
authors.initials: R
authors.lastname: Kreibich
authors.forename: Eva
authors.initials: E
authors.lastname: Weisz
authors.forename: Michaela
authors.initials: M
authors.lastname: Artwohl
authors.forename: Olaf C
authors.initials: OC
authors.lastname: Kleine
authors.forename: Mathias
authors.initials: M
authors.lastname: Muller
authors.forename: Sabina
authors.initials: S
authors.lastname: Baumgartner-Parzer
authors.forename: Jacques
authors.initials: J
authors.lastname: Ghysdael
authors.forename: Michael
authors.initials: M
authors.lastname: Freissmuth
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D000011:Abelson murine leukemia virus / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015448:Leukemia, B-Cell / Q000276:immunology* / Q000473:pathology; D007942:Leukemia, Experimental / Q000276:immunology* / Q000473:pathology; D015458:Leukemia, T-Cell / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000473:pathology; D015996:Survival Rate; D053634:TYK2 Kinase
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse