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

Sivahari Prasad Gorantla, Michael Rassner, Kirstyn Anne Crossley, Tony Andreas Müller, Teresa Poggio, Shifa Khaja Saleem, Helen Kleinfelder, Sudheer Madan Mohan Gambheer, Cornelia Endres, Sabina Schaberg, Dominik Schmidt, Gerin Prince, Irene Gonzalez-Menendez, Detlef Bentrop, Rainer Trittler, Svetlana Rylova, Dietmar Pfeifer, Geoffroy Andrieux, Leticia Quintanilla-Martinez, Anna Lena Illert, Nikolas Bubnoff, Robert Zeiser and Justus Duyster ()
Additional contact information
Sivahari Prasad Gorantla: University Medical Center Freiburg
Michael Rassner: University Medical Center Freiburg
Kirstyn Anne Crossley: University Medical Center Freiburg
Tony Andreas Müller: University Medical Center Freiburg
Teresa Poggio: University Medical Center Freiburg
Shifa Khaja Saleem: University Medical Center Freiburg
Helen Kleinfelder: University Medical Center Freiburg
Sudheer Madan Mohan Gambheer: University Medical Center Freiburg
Cornelia Endres: University Medical Center Freiburg
Sabina Schaberg: University Medical Center Freiburg
Dominik Schmidt: University Medical Center Freiburg
Gerin Prince: University Medical Center Schleswig-Holstein, and University Cancer Center Schleswig-Holstein
Irene Gonzalez-Menendez: University Hospital Tübingen & Comprehensive Cancer Center Tübingen
Detlef Bentrop: Albert-Ludwigs-Universität Freiburg
Rainer Trittler: Albert-Ludwigs-Universität Freiburg
Svetlana Rylova: University Medical Center Freiburg
Dietmar Pfeifer: University Medical Center Freiburg
Geoffroy Andrieux: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)
Leticia Quintanilla-Martinez: University Hospital Tübingen & Comprehensive Cancer Center Tübingen
Anna Lena Illert: University Medical Center Freiburg
Nikolas Bubnoff: University Medical Center Schleswig-Holstein, and University Cancer Center Schleswig-Holstein
Robert Zeiser: University Medical Center Freiburg
Justus Duyster: University Medical Center Freiburg

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60019-6

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