Janus kinase 2 inhibitors (JAKi) are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life (QoL). Allogeneic stem cell transplant is currently the only treatment modality in MF with the potential to cure the disease or prolong survival. By contrast, current drug therapy in MF targets QoL and does not modify the natural history of the disease. The discovery of JAK2 and other JAK-STAT activating mutations (i.e., CALR and MPL) in myeloproliferative neoplasms, including MF, has facilitated the development of several JAKi that are not necessarily specific to the oncogenic mutations themselves but proved effective in countering JAK-STAT signaling, resulting in suppression of inflammatory cytokines and myeloproliferation. This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, FDA approval of three small molecule JAKi: ruxolitinib, fedratinib, and pacritinib. A fourth JAKi, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusiondependent anemia in MF. The salutary effect of momelotinib on anemia has been attributed to inhibition of activin A receptor, type 1 (ACVR1) and recent information suggests similar effect from pacritinib. ACRV1 mediates SMAD2/3 signalling that contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Therapeutic targeting of ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of JAK2 mutation and thrombocytosis.

中文翻译：

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Momelotinib（JAK1/JAK2/ACVR1 抑制剂）：作用机制、临床试验报告以及骨髓纤维化以外的治疗前景。

Janus 激酶 2 抑制剂 (JAKi) 现在是原发性和继发性骨髓纤维化 (MF) 治疗药物的一部分。MF 患者的生存期缩短且生活质量 (QoL) 较差。同种异体干细胞移植是目前唯一有可能治愈该疾病或延长生存期的 MF 治疗方式。相比之下，目前 MF 的药物治疗以生活质量为目标，并且不会改变疾病的自然史。在骨髓增生性肿瘤（包括 MF）中发现 JAK2 和其他 JAK-STAT 激活突变（即 CALR 和 MPL），促进了几种 JAKi 的开发，这些 JAKi 不一定特定于致癌突变本身，但被证明可有效对抗 JAK-STAT信号传导，从而抑制炎症细胞因子和骨髓增殖。这种非特异性活性对全身症状和脾肿大产生了临床上有利的效果，因此 FDA 批准了三种小分子 JAKi：ruxolitinib、fedratinib 和 pacritinib。第四种 JAKi 莫洛替尼 (momelotinib) 即将获得 FDA 批准，并已被证明可以在缓解 MF 输血依赖性贫血方面提供额外益处。莫莫替尼对贫血的有益作用归因于对 1 型激活素 A 受体 (ACVR1) 的抑制，最近的信息表明帕克里替尼也有类似的作用。ACRV1 介导 SMAD2/3 信号传导，有助于上调铁调素的产生和铁限制性红细胞生成。ACRV1 的治疗靶向提高了与无效红细胞生成相关的其他骨髓肿瘤的治疗前景，例如伴有环状铁粒幼细胞或 SF3B1 突变的骨髓增生异常综合征，特别是那些同时表达 JAK2 突变和血小板增多症的骨髓增生异常综合征。