Journal Article

DKFZ-2025-01085

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling.

Gorantla, S. P. ; Rassner, M. ; Crossley, K. A. ; Müller, T. A. ; Poggio, T. ; Khaja Saleem, S. ; Kleinfelder, H. ; Gambheer, S. M. M. ; Endres, C. ; Schaberg, S. ; Schmidt, D. ; Prince, G. ; Gonzalez-Menendez, I. ; Bentrop, D. ; Trittler, R. ; Rylova, S. ; Pfeifer, D. ; Andrieux, G.DKFZ* ; Quintanilla-Martinez, L. ; Illert, A. L.DKFZ* ; von Bubnoff, N. ; Zeiser, R. ; Duyster, J.DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-60019-6

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.

Keyword(s): Animals (MeSH) ; Janus Kinase 2: antagonists & inhibitors (MeSH) ; Janus Kinase 2: genetics (MeSH) ; Janus Kinase 2: metabolism (MeSH) ; Nitriles (MeSH) ; Pyrazoles: pharmacology (MeSH) ; Pyrazoles: therapeutic use (MeSH) ; Pyrimidines (MeSH) ; Myeloproliferative Disorders: drug therapy (MeSH) ; Myeloproliferative Disorders: genetics (MeSH) ; Myeloproliferative Disorders: pathology (MeSH) ; Myeloproliferative Disorders: metabolism (MeSH) ; Mice (MeSH) ; Signal Transduction: drug effects (MeSH) ; Janus Kinase 1: antagonists & inhibitors (MeSH) ; Janus Kinase 1: genetics (MeSH) ; Janus Kinase 1: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Mutation (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; Protein Kinase Inhibitors: therapeutic use (MeSH) ; Cytokines: metabolism (MeSH) ; Cytokines: blood (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Humans (MeSH) ; Cell Proliferation: drug effects (MeSH) ; Mice, Inbred C57BL (MeSH) ; Female (MeSH) ; Spleen: drug effects (MeSH) ; Spleen: pathology (MeSH) ; Janus Kinase 2 ; ruxolitinib ; Nitriles ; Pyrazoles ; Pyrimidines ; Janus Kinase 1 ; Jak2 protein, mouse ; Protein Kinase Inhibitors ; Jak1 protein, mouse ; Cytokines

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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