Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies.
Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies.
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DOI：
10.1177/1947601910397187
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Reddy EP
中科院分区：
文献类型：
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作者：
Jatiani SS;Baker SJ;Silverman LR;Reddy EP
造血是由细胞因子及其受体介导的复杂调节的信号通路的累积结果。在过去10-15年进行的研究已经揭示，造血细胞因子受体信号传导主要由称为Janus激酶（JAK）的酪氨酸激酶家族及其下游转录因子，称为STAT（信号转导子和转录激活子）介导。这些通路的异常，如最近发现的JAK 2 V617 F突变和JAK 2基因易位引起的异常，是白血病和其他骨髓增生性疾病的根本原因。本文综述了JAK/STAT信号在正常造血以及骨髓增生和骨髓增生综合征中的作用。本文还总结了目前处于临床开发各个阶段的几种小分子JAK 2抑制剂的现状。这些化合物中的几种似乎通过减轻疾病相关症状来改善骨髓增生性疾病患者的生活质量。然而，到目前为止，这些药物似乎没有显着影响骨髓纤维化，改变骨髓组织病理学，逆转血细胞减少，减少红细胞输血的要求或显着降低等位基因负荷。这些结果表明，额外的突变事件可能与这些肿瘤的发展，并表明需要额外的治疗方法，因为这些额外的分子事件的性质是更好地理解。
Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Studies conducted over the past 10–15 years have revealed that hematopoietic cytokine receptor signaling is largely mediated by a family of tyrosine kinases termed Janus Kinases (JAKs) and their downstream transcription factors, termed STATs (signal transducers and activators of transcription). Aberrations in these pathways, such as those caused by the recently identified JAK2V617F mutation and translocations of the JAK2 gene, are underlying causes of leukemias and other myeloproliferative disorders. This review discusses the role of JAK/STAT signaling in normal hematopoiesis as well as myeloproliferative and myelodisplastic syndromes. This review also summarizes the status of several small molecule JAK2 inhibitors that are currently at various stages of clinical development. Several of these compounds appear to improve the quality of life of patients with myeloproliferative disorders by palliation of disease-related symptoms. However, to date, these agents do not seem to significantly affect bone marrow fibrosis, alter marrow histopathology, reverse cytopenias, reduce red cell transfusion requirements or significantly reduce allele burden. These results suggest that additional mutational events might be associated with the development of these neoplasms and indicate the need for additional therapeutic approaches as the nature of these additional molecular events is better understood.