Gorantla Sivahari Prasad, Rassner Michael, Crossley Kirstyn Anne, Müller Tony Andreas, Poggio Teresa, Khaja Saleem Shifa, Kleinfelder Helen, Gambheer Sudheer Madan Mohan, Endres Cornelia, Schaberg Sabina, Schmidt Dominik, Prince Gerin, Gonzalez-Menendez Irene, Bentrop Detlef, Trittler Rainer, Rylova Svetlana, Pfeifer Dietmar, Andrieux Geoffroy, Quintanilla-Martinez Leticia, Illert Anna Lena, von Bubnoff Nikolas, Zeiser Robert, Duyster Justus
Faculty of Medicine, Clinic for Internal Medicine I, Hematology, Oncology and Stem cell transplantation, University Medical Center Freiburg, Freiburg, Germany.
Department of Hematology and Oncology, University Medical Center Schleswig-Holstein, and University Cancer Center Schleswig-Holstein, Lübeck, Germany.
Nat Commun. 2025 May 24;16(1):4833. doi: 10.1038/s41467-025-60019-6.
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.
鲁索替尼是一种强效的JAK1/JAK2抑制剂，基于抑制致癌信号传导的概念被批准用于治疗原发性骨髓纤维化（PMF）患者。然而，鲁索替尼对JAK2-V617F等位基因负担的影响较小，这表明抑制JAK2-V617F信号驱动的克隆扩增不是其主要作用机制。我们评估鲁索替尼是否主要阻断恶性克隆的增殖，或者是否也通过靶向非恶性细胞发挥作用。因此，我们构建了两种携带鲁索替尼耐药突变的JAK2-V617F驱动的骨髓增殖性肿瘤（MPN）小鼠模型。携带鲁索替尼耐药的JAK2-V617F驱动的MPN的小鼠在脾脏大小、白细胞计数和血清促炎细胞因子降低方面，对鲁索替尼治疗的反应与携带鲁索替尼敏感的JAK2-V617F MPN的小鼠相似。鲁索替尼可降低基质细胞和非恶性造血细胞中的促炎细胞因子。通过一种严格的鲁索替尼耐药突变方法，我们可以证明鲁索替尼的作用独立于致癌性JAK2-V617F信号传导，并可减轻MPN疾病的主要特征，如脾脏大小和白细胞计数。我们的研究结果明确了鲁索替尼在MPN中的作用机制。
