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TYK2 is a key regulator of the surveillance of B lymphoid tumors
Dagmar Stoiber, … , Michael Freissmuth, Veronika Sexl
Dagmar Stoiber, … , Michael Freissmuth, Veronika Sexl
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1650-1658. https://doi.org/10.1172/JCI22315.
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Article Oncology

TYK2 is a key regulator of the surveillance of B lymphoid tumors

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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

Dagmar Stoiber, Boris Kovacic, Christian Schuster, Carola Schellack, Marina Karaghiosoff, Rita Kreibich, Eva Weisz, Michaela Artwohl, Olaf C. Kleine, Mathias Muller, Sabina Baumgartner-Parzer, Jacques Ghysdael, Michael Freissmuth, Veronika Sexl

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Figure 5

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In vitro characterization of TYK2+/– and TYK2–/– NK/NKT cells. (A) An MT...
In vitro characterization of TYK2+/– and TYK2–/– NK/NKT cells. (A) An MTT assay did not reveal any differences in growth characteristics of TYK2+/+-derived and TYK2–/–-derived NK/NKT cells. Each data point represents mean ± SD from 5 individual wells. One representative experiment is depicted (n = 3). (B) Similarly, FACS analysis of the in vitro_derived cells showed a comparable composition of NK (NK1.1+CD3–) and NKT (NK1.1+CD3+) cells, with an estimate of 20% NKT cells. One representative experiment is depicted (n = 6 for each genotype). (C) Production of IFN-γ in NK/NKT cells after expansion with IL-2. NK/NKT cells were either left untreated or incubated with IL-12 or IL-2 for 48 hours. Culture supernatants were analyzed for IFN-γ production by ELISA. One representative experiment is shown (n = 4). (D) RT-PCR and subsequent oligohybridization for IFN-γ from TYK2+/–-derived and TYK2–/–-derived tumors. Representative examples of the analysis are shown in the upper panel. Activated (IL-2 and anti-CD3) primary T lymphocytes were used as positive control (Co). An RT-PCR reaction for β-actin was performed to control for the prepared cDNA. IFN-γ was only detected in tumors derived from TYK2+/– animals. (E) Cytotoxicity assay using TYK2+/+ and TYK2–/– NK/NKT cells as effector and YAC-1 cells as target cells. One representative experiment is shown (n = 4). TYK2–/– NK/NKT cells were consistently less efficient in lysing YAC-1 cells. E/T, effector/target; conc., concentration.

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