Merchant Akil, Chaudhry Parvesh, Singh Mohan, Lemos Tucker, Fargal Eman, Siddiqi Imran, O'Connell Casey, Zhao Zhizhuang
Cedars-Sinai Medical Center.
University of Southern California.
Res Sq. 2025 May 9:rs.3.rs-6580439. doi: 10.21203/rs.3.rs-6580439/v1.
Treatment of JAK2V617F driven myeloproliferative neoplasms (MPNs) with Ruxolitinib (JAK inhibitor, JAKi) has shown limited disease-modifying benefits and has led to the search for other pathways as potential therapeutic targets for this disease. We investigated the effects of Smoothened inhibition (SMOi) using the small-molecule inhibitor PF-04449913 (PF-13) in a JAK2V617F transgenic mouse model that recapitulates many of the phenotypes of MPNs including bone marrow fibrosis and splenomegaly. We show both that hedgehog (Hh) signaling pathway is activated in JAK2V617F cells and that SMOi reduces splenomegaly in JAK2V617F mice. In a murine bone marrow transplant model, we show that SMOi also reduces JAK2V617F allelic burden. JAK2V617F mice show increased pERK and NF-κB signaling, which is reduced with SMOi. Finally, we found that SMO inhibitor blocks bone marrow fibrosis by reducing TGF-β signaling. In conclusion, this report provides critical insight into the mechanism of action of SMO inhibitors in JAK2V617F associated MPN.
用芦可替尼（一种JAK抑制剂，JAKi）治疗JAK2V617F驱动的骨髓增殖性肿瘤（MPN）已显示出有限的疾病改善益处，这促使人们寻找其他途径作为该疾病的潜在治疗靶点。我们在一种JAK2V617F转基因小鼠模型中研究了使用小分子抑制剂PF-04449913（PF-13）抑制Smoothened（SMOi）的效果，该模型再现了MPN的许多表型，包括骨髓纤维化和脾肿大。我们发现，在JAK2V617F细胞中刺猬（Hh）信号通路被激活，并且SMOi可减轻JAK2V617F小鼠的脾肿大。在小鼠骨髓移植模型中，我们发现SMOi还可降低JAK2V617F等位基因负荷。JAK2V617F小鼠显示pERK和NF-κB信号增加，而SMOi可使其降低。最后，我们发现SMO抑制剂通过减少TGF-β信号传导来阻断骨髓纤维化。总之，本报告为SMO抑制剂在JAK2V617F相关MPN中的作用机制提供了关键见解。
