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：

---

莫莫替尼（JAK1/JAK2/ACVR1 抑制剂）：作用机制、临床试验报告和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） 治疗武器的一部分。MF 患者生存期缩短，生活质量 （QoL） 差。同种异体干细胞移植是目前 MF 中唯一有可能治愈疾病或延长生存期的治疗方式。相比之下，目前 MF 的药物治疗针对 QoL，不会改变疾病的自然病程。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 的发展，这些 JAKi 不一定对致癌突变本身具有特异性，但被证明可有效对抗 JAK-STAT 信号传导，从而抑制炎性细胞因子和骨髓增生。这种非特异性活性导致对全身症状和脾肿大产生临床上有利的影响，因此，FDA 批准了三种小分子 JAKi：ruxolitinib、fedratinib 和 pacritinib。第四种 JAKi，莫莫替尼，即将获得 FDA 批准，并已被证明在缓解 MF 输血依赖性贫血方面提供额外的益处。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 pacritinib 也有类似的效果。ACRV1 介导 SMAD2/3 信号传导，有助于铁调素生成和铁限制性红细胞生成上调。ACRV1 的治疗靶向提高了其他与无效红细胞生成相关的髓系肿瘤的治疗前景，例如具有环形铁粒幼细胞或 SF3B1 突变的骨髓增生异常综合征，尤其是那些具有 JAK2 突变和血小板增多症共表达的骨髓增生异常综合征。