Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR-146a, a negative regulator of the NF-κB pathway, in the pathogenesis of MF; here we used miR-146a^−/− (KO) mice, a MF-like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF-κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF-κB inhibition, either using BMS-345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL-1β and TNFα). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF-κB and JAK/STAT signaling in a context of JAK2V617F-driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.

中文翻译：

---

miR-146a−/− 小鼠模型揭示 NF-κB 抑制可逆转炎症驱动的骨髓纤维化样表型


新的证据表明炎症（特别是 NF-κB 通路）在骨髓纤维化 (MF) 的发生和进展中发挥着至关重要的作用，成为一个有前途的治疗靶点。此外，使用目前可用的 JAK 抑制剂（例如 ruxolitinib 或 fedratinib）进行定制治疗不会改变疾病的自然史，并且具有重要的局限性，包括血细胞减少症。最近的研究强调了 miR-146a（NF-κB 通路的负调节因子）在 MF 发病机制中的作用；在这里，我们使用 miR-146a ^−/− (KO) 小鼠（一种缺乏驱动突变的 MF 样模型）来研究 JAK/STAT 和/或 NF-κB 通路的药理学抑制是否可以逆转这些小鼠的骨髓纤维化表型老鼠。具体来说，我们测试了 JAK1/2 抑制剂 ruxolitinib；通过 IKKα/β 的 NF-κB 抑制剂，BMS-345541；两种抑制剂的组合；或两种途径的双重抑制剂 (JAK2/IRAK1)，pacritinib。尽管所有治疗均减小了脾脏大小并部分恢复了其结构，但仅使用 BMS-345541（单独或联合）或 pacritinib 抑制 NF-κB 会导致髓外造血、骨髓 (BM) 纤维化和骨质硬化减少，同时减轻加剧的炎症状态（通过 IL-1β 和 TNFα）。然而，虽然双重抑制剂改善了贫血并逆转了血小板减少症，但联合治疗通过诱导骨髓发育不全而恶化了贫血。在 JAK2V617F 驱动的克隆造血过程中，两种治疗方案均减少了 NF-κB 和 JAK/STAT 信号传导。此外，在模拟 JAK2 驱动的纤维化的体外模型中，联合治疗减少了 COL1A1 和 IL-6 的产生。 总之，NF-κB 抑制在体外和体内均可减轻疾病负担和骨髓纤维化，这可以为骨髓纤维化患者带来益处。