TY  - JOUR
AU  - Gorantla, Sivahari Prasad
AU  - Rassner, Michael
AU  - Crossley, Kirstyn Anne
AU  - Müller, Tony Andreas
AU  - Poggio, Teresa
AU  - Khaja Saleem, Shifa
AU  - Kleinfelder, Helen
AU  - Gambheer, Sudheer Madan Mohan
AU  - Endres, Cornelia
AU  - Schaberg, Sabina
AU  - Schmidt, Dominik
AU  - Prince, Gerin
AU  - Gonzalez-Menendez, Irene
AU  - Bentrop, Detlef
AU  - Trittler, Rainer
AU  - Rylova, Svetlana
AU  - Pfeifer, Dietmar
AU  - Andrieux, Geoffroy
AU  - Quintanilla-Martinez, Leticia
AU  - Illert, Anna Lena
AU  - von Bubnoff, Nikolas
AU  - Zeiser, Robert
AU  - Duyster, Justus
TI  - Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01085
SP  - 4833
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Janus Kinase 2: antagonists & inhibitors
KW  - Janus Kinase 2: genetics
KW  - Janus Kinase 2: metabolism
KW  - Nitriles
KW  - Pyrazoles: pharmacology
KW  - Pyrazoles: therapeutic use
KW  - Pyrimidines
KW  - Myeloproliferative Disorders: drug therapy
KW  - Myeloproliferative Disorders: genetics
KW  - Myeloproliferative Disorders: pathology
KW  - Myeloproliferative Disorders: metabolism
KW  - Mice
KW  - Signal Transduction: drug effects
KW  - Janus Kinase 1: antagonists & inhibitors
KW  - Janus Kinase 1: genetics
KW  - Janus Kinase 1: metabolism
KW  - Disease Models, Animal
KW  - Mutation
KW  - Protein Kinase Inhibitors: pharmacology
KW  - Protein Kinase Inhibitors: therapeutic use
KW  - Cytokines: metabolism
KW  - Cytokines: blood
KW  - Drug Resistance, Neoplasm: genetics
KW  - Humans
KW  - Cell Proliferation: drug effects
KW  - Mice, Inbred C57BL
KW  - Female
KW  - Spleen: drug effects
KW  - Spleen: pathology
KW  - Janus Kinase 2 (NLM Chemicals)
KW  - ruxolitinib (NLM Chemicals)
KW  - Nitriles (NLM Chemicals)
KW  - Pyrazoles (NLM Chemicals)
KW  - Pyrimidines (NLM Chemicals)
KW  - Janus Kinase 1 (NLM Chemicals)
KW  - Jak2 protein, mouse (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
KW  - Jak1 protein, mouse (NLM Chemicals)
KW  - Cytokines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40413183
DO  - DOI:10.1038/s41467-025-60019-6
UR  - https://inrepo02.dkfz.de/record/301577
ER  -