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@ARTICLE{Gorantla:301577,
      author       = {S. P. Gorantla and M. Rassner and K. A. Crossley and T. A.
                      Müller and T. Poggio and S. Khaja Saleem and H. Kleinfelder
                      and S. M. M. Gambheer and C. Endres and S. Schaberg and D.
                      Schmidt and G. Prince and I. Gonzalez-Menendez and D.
                      Bentrop and R. Trittler and S. Rylova and D. Pfeifer and G.
                      Andrieux$^*$ and L. Quintanilla-Martinez and A. L.
                      Illert$^*$ and N. von Bubnoff and R. Zeiser and J.
                      Duyster$^*$},
      title        = {{E}fficacy of {JAK}1/2 inhibition in murine
                      myeloproliferative neoplasms is not mediated by targeting
                      oncogenic signaling.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-01085},
      pages        = {4833},
      year         = {2025},
      abstract     = {Ruxolitinib is a potent JAK1/JAK2 inhibitor, approved for
                      the treatment of primary myelofibrosis (PMF) patients based
                      on the concept of inhibition of oncogenic signaling.
                      However, the effect of ruxolitinib on JAK2-V617F allelic
                      burden is modest, suggesting that inhibition of JAK2-V617F
                      signaling-driven clone expansion is not the main mechanism
                      of action. We evaluate whether ruxolitinib mainly blocks the
                      proliferation of the malignant clone or exerts its effects
                      also by targeting non-malignant cells. Therefore, we develop
                      two JAK2-V617F-driven myeloproliferative neoplasm (MPN)
                      mouse models harboring ruxolitinib resistance mutations.
                      Mice carrying ruxolitinib-resistant JAK2-V617F-driven MPN
                      respond to ruxolitinib treatment similar to mice with
                      ruxolitinib-sensitive JAK2-V617F MPN with respect to
                      reduction of spleen size, leukocyte count and
                      pro-inflammatory cytokines in the serum. Ruxolitinib reduces
                      pro-inflammatory cytokines in both stromal cells and
                      non-malignant hematopoietic cells. Using a rigorous
                      ruxolitinib resistance mutation approach, we can prove that
                      ruxolitinib acts independent of oncogenic JAK2-V617F
                      signaling and reduces the main features of MPN disease such
                      as spleen size and leukocyte counts. Our findings
                      characterize the mechanism of action for ruxolitinib in
                      MPN.},
      keywords     = {Animals / Janus Kinase 2: antagonists $\&$ inhibitors /
                      Janus Kinase 2: genetics / Janus Kinase 2: metabolism /
                      Nitriles / Pyrazoles: pharmacology / Pyrazoles: therapeutic
                      use / Pyrimidines / Myeloproliferative Disorders: drug
                      therapy / Myeloproliferative Disorders: genetics /
                      Myeloproliferative Disorders: pathology / Myeloproliferative
                      Disorders: metabolism / Mice / Signal Transduction: drug
                      effects / Janus Kinase 1: antagonists $\&$ inhibitors /
                      Janus Kinase 1: genetics / Janus Kinase 1: metabolism /
                      Disease Models, Animal / Mutation / Protein Kinase
                      Inhibitors: pharmacology / Protein Kinase Inhibitors:
                      therapeutic use / Cytokines: metabolism / Cytokines: blood /
                      Drug Resistance, Neoplasm: genetics / Humans / Cell
                      Proliferation: drug effects / Mice, Inbred C57BL / Female /
                      Spleen: drug effects / Spleen: pathology / Janus Kinase 2
                      (NLM Chemicals) / ruxolitinib (NLM Chemicals) / Nitriles
                      (NLM Chemicals) / Pyrazoles (NLM Chemicals) / Pyrimidines
                      (NLM Chemicals) / Janus Kinase 1 (NLM Chemicals) / Jak2
                      protein, mouse (NLM Chemicals) / Protein Kinase Inhibitors
                      (NLM Chemicals) / Jak1 protein, mouse (NLM Chemicals) /
                      Cytokines (NLM Chemicals)},
      cin          = {FR01},
      ddc          = {500},
      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:40413183},
      doi          = {10.1038/s41467-025-60019-6},
      url          = {https://inrepo02.dkfz.de/record/301577},
}