Raivola Juuli, Haikarainen Teemu, Abraham Bobin George, Silvennoinen Olli
Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland.
Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
Cancers (Basel). 2021 Feb 14;13(4):800. doi: 10.3390/cancers13040800.
Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregulation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are activating somatic mutations and less frequently translocations resulting in constitutively active JAK fusion proteins. JAKs have become important therapeutic targets and currently, six JAK inhibitors have been approved by the FDA for the treatment of both autoimmune diseases and hematological malignancies. However, the efficacy of the current drugs is not optimal and the full potential of JAK modulators in leukemia is yet to be harnessed. This review discusses the deregulation of JAK-STAT signaling that underlie the pathogenesis of leukemia, i.e., mutations and other mechanisms causing hyperactive cytokine signaling, as well as JAK inhibitors used in clinic and under clinical development.
Janus激酶（JAKs）可转导来自数十种细胞外细胞因子的信号，并作为细胞生长、分化、基因表达和免疫反应的关键调节因子。JAK/STAT信号通路失调是包括各种类型白血病和其他恶性肿瘤以及自身免疫性疾病在内的多种人类疾病的核心组成部分。不同类型的白血病在所有四种JAKs（JAK1、JAK2、JAK3和TYK2）中都存在基因组畸变，其中大多数是激活体细胞突变，较少见的是导致组成型活性JAK融合蛋白的易位。JAKs已成为重要的治疗靶点，目前已有六种JAK抑制剂获得美国食品药品监督管理局（FDA）批准，用于治疗自身免疫性疾病和血液系统恶性肿瘤。然而，目前药物的疗效并不理想，JAK调节剂在白血病治疗中的全部潜力尚未得到充分发挥。本综述讨论了白血病发病机制中JAK-STAT信号通路失调，即导致细胞因子信号过度活跃的突变和其他机制，以及临床应用和正在进行临床开发的JAK抑制剂。
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