Jatiani Shashidhar S, Baker Stacey J, Silverman Lewis R, Reddy E Premkumar
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA.
Genes Cancer. 2010 Oct;1(10):979-93. doi: 10.1177/1947601910397187.
Hematopoiesis is the cumulative result of intricately regulated signaling pathways that are mediated by cytokines and their receptors. Studies conducted over the past 10 to 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 JAK2(V617F) 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 genetic abnormalities associated with 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 the possibility that additional mutational events might be associated with the development of these neoplasms, and indicate the need for combination therapies as the nature and significance of these additional molecular events is better understood.
造血作用是由细胞因子及其受体介导的复杂调控信号通路的累积结果。过去10至15年进行的研究表明，造血细胞因子受体信号传导很大程度上由一类称为Janus激酶（JAKs）的酪氨酸激酶及其下游转录因子（称为信号转导子和转录激活子，即STATs）介导。这些信号通路的异常，例如最近发现的JAK2（V617F）突变和JAK2基因易位所导致的异常，是白血病和其他骨髓增殖性疾病的根本原因。本综述讨论了JAK/STAT信号传导在正常造血中的作用以及与骨髓增殖性和骨髓增生异常综合征相关的基因异常。本综述还总结了目前处于临床开发不同阶段的几种小分子JAK2抑制剂的情况。其中几种化合物似乎通过缓解疾病相关症状改善了骨髓增殖性疾病患者的生活质量。然而，迄今为止，这些药物似乎并未显著影响骨髓纤维化、改变骨髓组织病理学、逆转血细胞减少、减少红细胞输血需求或显著降低等位基因负担。这些结果表明，可能还有其他突变事件与这些肿瘤的发生有关，并表明随着对这些额外分子事件的性质和意义有更好的了解，需要采用联合疗法。
