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@ARTICLE{Jaeger:212478,
      author       = {A. Jaeger and S. M. M. Gambheer and X. Sun and D.
                      Chernyakov and O. Skorobohatko and T. M. Mack and S. Kissel
                      and D. Pfeifer and R. Zeiser and P. Fisch and G. Andrieux
                      and D. Bräuer-Hartmann and M. Bauer and S. Schulze and M.
                      Follo and M. Börries$^*$ and N. von Bubnoff and C. Miething
                      and J. V. Hidalgo and C. Klein and T. Weber and C.
                      Wickenhauser and M. Binder and C. Dierks},
      title        = {{A}ctivated granulocytes and inflammatory cytokine
                      signaling drive {T}-cell lymphoma progression and disease
                      symptoms.},
      journal      = {Blood},
      volume       = {141},
      number       = {23},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2023-00186},
      pages        = {2824-2840},
      year         = {2023},
      note         = {2023 Jun 8;141(23):2824-2840},
      abstract     = {Peripheral T-cell lymphomas (PTCL) - especially
                      angioimmunoblastic (AITL) and follicular TCL - have a dismal
                      prognosis due to lack of efficient therapies, and patients`
                      symptoms are often dominated by an inflammatory phenotype
                      including fever, night sweats, weight loss and skin rash. In
                      this study, we investigated the role of inflammatory
                      granulocytes and activated cytokine signaling on PTCL-TFH
                      (T-follicular helper type) disease progression and symptoms.
                      We show, that ITK-SYK driven murine PTCLs and primary human
                      PTCL-TFH xenografts both induce inflammation in mice
                      including murine neutrophil expansion and massive cytokine
                      release. Granulocyte/lymphoma interactions were mediated by
                      positive autoregulatory cytokine loops involving INF-γ
                      (CD4+malignant T-cells) and IL-6 (activated granulocytes),
                      ultimately inducing broad JAK kinase activation (Jak1/2/3,
                      Tyk2) in both cell types. Depletion of inflammatory
                      granulocytes via antibodies (Ly6G), genetic granulocyte
                      depletion (LyzM-Cre/MCL1flox/flox) or the deletion of IL-6
                      within microenvironmental cells blocked inflammatory
                      symptoms, reduced lymphoma infiltration and enhanced mouse
                      survival. Furthermore, unselective JAK kinase inhibitors
                      (ruxolitinib) inhibited both, TCL progression and
                      granulocyte activation in various PTCL mouse models. Our
                      results support the important role of granulocyte-driven
                      inflammation, cytokine-induced granulocyte/CD4+ TCL
                      interactions and the requirement of an intact JAK/STAT
                      signaling pathway for PTCL-TFH development, and support
                      broad JAK kinase inhibition as an effective treatment
                      strategy in early disease stages.},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36696631},
      doi          = {10.1182/blood.2022015653},
      url          = {https://inrepo02.dkfz.de/record/212478},
}