TYK2 is a key regulator of the surveillance of B lymphoid tumors.
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.
Stoiber
Dagmar
D
Department of Pharmacology, Medical University of Vienna, Vienna, Austria.
Kovacic
Boris
B
Schuster
Christian
C
Schellack
Carola
C
Karaghiosoff
Marina
M
Kreibich
Rita
R
Weisz
Eva
E
Artwohl
Michaela
M
Kleine
Olaf C
OC
Muller
Mathias
M
Baumgartner-Parzer
Sabina
S
Ghysdael
Jacques
J
Freissmuth
Michael
M
Sexl
Veronika
V
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
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