Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents
Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and ameliorates anemia of chronic disease in rodents
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DOI：
10.1182/blood-2016-09-740092
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发表时间：
2017-03-30
期刊：
影响因子：
20.3
通讯作者：
Theurl, Igor
中科院分区：
文献类型：
--
作者：
Asshoff, Malte;Petzer, Verena;Theurl, Igor
骨髓纤维化（MF）患者经常发生贫血，并经常依赖于红细胞输注。用Janus激酶1/2（JAK 1/2）抑制剂momelotinib（MMB）治疗MF的2期研究结果表明，MMB治疗改善了贫血，这对于JAK 1/2抑制剂来说是出乎意料的，因为红细胞生成素介导的JAK 2信号传导对红细胞生成至关重要。使用慢性疾病贫血的大鼠模型，我们证明了MMB治疗可以使血红蛋白和红细胞数量正常化。我们发现，这种积极的影响是由骨形态发生蛋白受体激酶激活素A受体，I型（ACVR 1）的直接抑制，并随后减少肝细胞hepcidin的生产。值得注意的是，批准用于治疗MF的JAK 1/2抑制剂ruxolitinib对该途径没有抑制活性。此外，我们证明了MMB的作用不是通过直接抑制JAK 2介导的铁转运蛋白（FPN 1）降解介导的，因为MMB治疗和JAK 2的骨髓特异性缺失都不影响FPN 1的表达。我们的数据支持这一假设，即MMB改善炎性贫血是由于抑制ACVR 1介导的肝铁调素表达，这导致从细胞储存中螯合铁的动员增加，随后刺激红细胞生成。
Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Results from a phase 2 study for the treatment of MF with the Janus kinase 1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, which was unexpected for a JAK1/2 inhibitor, because erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease, we demonstrated that MMB treatment can normalize hemoglobin and red blood cell numbers. We found that this positive effect is driven by direct inhibition of the bone morphogenic protein receptor kinase activin A receptor, type I (ACVR1), and the subsequent reduction of hepatocyte hepcidin production. Of note, ruxolitinib, a JAK1/2 inhibitor approved for the treatment of MF, had no inhibitory activity on this pathway. Further, we demonstrated the effect of MMB is not mediated by direct inhibition of JAK2-mediated ferroportin (FPN1) degradation, because neitherMMB treatment nor myeloid-specific deletion of JAK2 affected FPN1 expression. Our data support the hypothesis that the improvement of inflammatory anemia by MMB results from inhibition of ACVR1-mediated hepcidin expression in the liver, which leads to increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis.