Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling

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.

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Publication Details

Journal
Nature Communications
Published
2025-05-24
DOI
https://doi.org/10.1038/s41467-025-60019-6
Citations
4
Primary Topic
Myeloproliferative Neoplasms: Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
6.50

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article

Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling

Cornelia Endres, Dietmar Pfeifer, Sudheer Madan Mohan Gambheer, Kirstyn Anne Crossley et al.
4 citations
Nature Communications
Myeloproliferative Neoplasms: Diagnosis and Treatment
6.50
article

Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling

Cornelia Endres, Dietmar Pfeifer, Sudheer Madan Mohan Gambheer, Kirstyn Anne Crossley, Tony Andreas Müller, Leticia Quintanilla-Martı́nez, Detlef Bentrop, Dominik Schmidt, Rainer Trittler, Teresa Poggio, Helen Kleinfelder, Geoffroy Andrieux, Svetlana N. Rylova, Gerin Prince, Nikolas C. C. von Bubnoff, Irene González-Menéndez, Michael Rassner, Robert Zeiser, Shifa Khaja Saleem, Sivahari Prasad Gorantla, Justus Duyster, Anna Lena Illert, Sabina Schaberg
article en
4 citations

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.

Nature CommunicationsVol. 16(1)
University of Freiburg (DE), German Cancer Research Center (DE), Kyoto University (JP), Heidelberg University (DE), University Medical Center Freiburg (DE), Integrated Oncology (United States) (US), University Hospital Schleswig-Holstein (DE), University Children's Hospital Tübingen (DE), University of Tübingen (DE), University of Lübeck (DE)
Deutsche Forschungsgemeinschaft
Good health and well-being
Openalex Percentile: Top 4%
Myeloproliferative Neoplasms: Diagnosis and Treatment
6.50
DOIOpen Access PDFOpenAlex
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