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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月24日

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  • 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

摘要

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.