Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications.
Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications.
复制标题
DOI：
10.3324/haematol.2020.262691
复制
发表时间：
2021-05-01
期刊：
影响因子：
10.1
通讯作者：
Thomas D
中科院分区：
文献类型：
--
作者：
Ross DM;Babon JJ;Tvorogov D;Thomas D
JAK-STAT信号的激活是骨髓纤维化的标志之一，这是一种骨髓增生性肿瘤，会导致炎症、进行性骨髓衰竭和白血病转化的风险。大约90%的骨髓纤维化患者在JAK2、MPL或CALR中存在突变：即所谓的导致JAK2激活的“驱动”突变。Ruxolitinib和临床上使用的其他JAK2抑制剂提供了临床益处，但对异常的造血克隆没有重大影响。这种现象被称为“坚持”，与通常的抵抗模式形成对比。多个小组已经证明，JAK2的1型抑制剂与酶的活性构象结合，导致JAK2对降解产生抵抗力，从而积累磷酸化的JAK2。反过来，当JAK抑制剂停止使用时，这可能会导致炎症表现的加剧，也可能有助于疾病的持久性。JAK2 V617F和CALR突变导致JAK-STAT信号激活的方式尚不完全清楚。我们总结了关于骨髓纤维化中病理性JAK-STAT激活的已知情况，以及这如何可能导致未来具有更大的疾病修改潜力的骨髓纤维化的新疗法。
Activation of JAK-STAT signaling is one of the hallmarks of myelofibrosis, a myeloproliferative neoplasm that leads to inflammation, progressive bone marrow failure, and a risk of leukemic transformation. Around 90% of patients with myelofibrosis have a mutation in JAK2, MPL, or CALR: so-called ‘driver’ mutations that lead to activation of JAK2. Ruxolitinib, and other JAK2 inhibitors in clinical use, provide clinical benefit but do not have a major impact on the abnormal hematopoietic clone. This phenomenon is termed ‘persistence’, in contrast to usual patterns of resistance. Multiple groups have shown that type 1 inhibitors of JAK2, which bind the active conformation of the enzyme, lead to JAK2 becoming resistant to degradation with consequent accumulation of phospho-JAK2. In turn, this can lead to exacerbation of inflammatory manifestations when the JAK inhibitor is discontinued, and it may also contribute to disease persistence. The ways in which JAK2 V617F and CALR mutations lead to activation of JAK-STAT signaling are incompletely understood. We summarize what is known about pathological JAK-STAT activation in myelofibrosis and how this might lead to future novel therapies for myelofibrosis with greater disease-modifying potential.