Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling
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 sign...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60019-6 |
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| author | 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 von Bubnoff Robert Zeiser Justus Duyster |
| author_facet | 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 von Bubnoff Robert Zeiser Justus Duyster |
| author_sort | Sivahari Prasad Gorantla |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-db668830e3404d6b98b3f64d80bb55c9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-db668830e3404d6b98b3f64d80bb55c92025-08-20T03:48:18ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-60019-6Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signalingSivahari Prasad Gorantla0Michael Rassner1Kirstyn Anne Crossley2Tony Andreas Müller3Teresa Poggio4Shifa Khaja Saleem5Helen Kleinfelder6Sudheer Madan Mohan Gambheer7Cornelia Endres8Sabina Schaberg9Dominik Schmidt10Gerin Prince11Irene Gonzalez-Menendez12Detlef Bentrop13Rainer Trittler14Svetlana Rylova15Dietmar Pfeifer16Geoffroy Andrieux17Leticia Quintanilla-Martinez18Anna Lena Illert19Nikolas von Bubnoff20Robert Zeiser21Justus Duyster22Faculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgDepartment of Hematology and Oncology, University Medical Center Schleswig-Holstein, and University Cancer Center Schleswig-HolsteinDepartment of Pathology and Neuropathology, University Hospital Tübingen & Comprehensive Cancer Center TübingenInstitute of Physiology, Albert-Ludwigs-Universität FreiburgInstitute of Pharmaceutical Sciences, Albert-Ludwigs-Universität FreiburgFaculty of Medicine, Department of Nuclear Medicine, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgGerman Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)Department of Pathology and Neuropathology, University Hospital Tübingen & Comprehensive Cancer Center TübingenFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgDepartment of Hematology and Oncology, University Medical Center Schleswig-Holstein, and University Cancer Center Schleswig-HolsteinFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgFaculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center FreiburgAbstract 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.https://doi.org/10.1038/s41467-025-60019-6 |
| spellingShingle | 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 von Bubnoff Robert Zeiser Justus Duyster Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling Nature Communications |
| title | Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling |
| title_full | Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling |
| title_fullStr | Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling |
| title_full_unstemmed | Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling |
| title_short | Efficacy of JAK1/2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling |
| title_sort | efficacy of jak1 2 inhibition in murine myeloproliferative neoplasms is not mediated by targeting oncogenic signaling |
| url | https://doi.org/10.1038/s41467-025-60019-6 |
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