Scott Linda M, Gandhi Maher K
University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.
University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia; Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia.
Blood Rev. 2015 Nov;29(6):405-15. doi: 10.1016/j.blre.2015.06.002. Epub 2015 Jun 11.
Gene expression profiling has implicated several intracellular signalling cascades, including the JAK/STAT pathway, in the pathogenesis of particular subtypes of lymphoma. In marked contrast to the situation in patients with either acute lymphoblastic leukaemia or a myeloproliferative neoplasm, JAK2 coding sequence mutations are rare in lymphoma patients with an activated JAK/STAT "signature". This is instead the consequence of mutational events that result in the increased expression of non-mutated JAK2; positively or negatively affect the activity of other components of the JAK/STAT pathway; or establish an autocrine signalling loop that drives JAK-mediated cytokine-independent proliferation. Here, we detail these genetic lesions, their functional consequences, and impact on patient outcome. In light of the approval of a JAK1/JAK2 inhibitor for the treatment of myelofibrosis, and preliminary studies evaluating the efficacy of other JAK inhibitors, the therapeutic potential of compounds that target JAK/STAT signalling in the treatment of patients with lymphoma is also discussed.
基因表达谱分析表明，包括JAK/STAT通路在内的几种细胞内信号级联反应与特定亚型淋巴瘤的发病机制有关。与急性淋巴细胞白血病或骨髓增殖性肿瘤患者的情况形成鲜明对比的是，在具有激活的JAK/STAT“特征”的淋巴瘤患者中，JAK2编码序列突变很少见。相反，这是由导致未突变的JAK2表达增加、正向或负向影响JAK/STAT通路其他成分的活性或建立驱动JAK介导的细胞因子非依赖性增殖的自分泌信号环的突变事件所致。在这里，我们详细介绍了这些基因损伤、它们的功能后果以及对患者预后的影响。鉴于一种JAK1/JAK2抑制剂已被批准用于治疗骨髓纤维化，并且有初步研究评估了其他JAK抑制剂的疗效，本文还讨论了靶向JAK/STAT信号的化合物在淋巴瘤患者治疗中的潜在治疗价值。
