%0 Journal Article
%A Gorantla, Sivahari Prasad
%A Rassner, Michael
%A Crossley, Kirstyn Anne
%A Müller, Tony Andreas
%A Poggio, Teresa
%A Khaja Saleem, Shifa
%A Kleinfelder, Helen
%A Gambheer, Sudheer Madan Mohan
%A Endres, Cornelia
%A Schaberg, Sabina
%A Schmidt, Dominik
%A Prince, Gerin
%A Gonzalez-Menendez, Irene
%A Bentrop, Detlef
%A Trittler, Rainer
%A Rylova, Svetlana
%A Pfeifer, Dietmar
%A Andrieux, Geoffroy
%A Quintanilla-Martinez, Leticia
%A Illert, Anna Lena
%A von Bubnoff, Nikolas
%A Zeiser, Robert
%A Duyster, Justus
%T Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-01085
%P 4833
%D 2025
%X 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.
%K Animals
%K Janus Kinase 2: antagonists & inhibitors
%K Janus Kinase 2: genetics
%K Janus Kinase 2: metabolism
%K Nitriles
%K Pyrazoles: pharmacology
%K Pyrazoles: therapeutic use
%K Pyrimidines
%K Myeloproliferative Disorders: drug therapy
%K Myeloproliferative Disorders: genetics
%K Myeloproliferative Disorders: pathology
%K Myeloproliferative Disorders: metabolism
%K Mice
%K Signal Transduction: drug effects
%K Janus Kinase 1: antagonists & inhibitors
%K Janus Kinase 1: genetics
%K Janus Kinase 1: metabolism
%K Disease Models, Animal
%K Mutation
%K Protein Kinase Inhibitors: pharmacology
%K Protein Kinase Inhibitors: therapeutic use
%K Cytokines: metabolism
%K Cytokines: blood
%K Drug Resistance, Neoplasm: genetics
%K Humans
%K Cell Proliferation: drug effects
%K Mice, Inbred C57BL
%K Female
%K Spleen: drug effects
%K Spleen: pathology
%K Janus Kinase 2 (NLM Chemicals)
%K ruxolitinib (NLM Chemicals)
%K Nitriles (NLM Chemicals)
%K Pyrazoles (NLM Chemicals)
%K Pyrimidines (NLM Chemicals)
%K Janus Kinase 1 (NLM Chemicals)
%K Jak2 protein, mouse (NLM Chemicals)
%K Protein Kinase Inhibitors (NLM Chemicals)
%K Jak1 protein, mouse (NLM Chemicals)
%K Cytokines (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40413183
%R 10.1038/s41467-025-60019-6
%U https://inrepo02.dkfz.de/record/301577