Boudny M, Trbusek M
Klin Onkol. 2020 Winter;33(1):32-38. doi: 10.14735/amko202032.
Signal transducer and activator of transcription (STAT) proteins are cytoplasmic transcription factors that transmit the signal of cytokines, hormones and growth factors. STAT proteins control fundamental cellular processes including survival, proliferation and differentiation. Inappropriate activation of STATs might contribute to cellular transformation and leukaemogenesis. About 70% of all solid and haematological tumours exhibit aberrant STAT3 expression and/or activation, highlighting its essential role in tumourigenesis. Aberrant STAT3 activation has been found in several solid tumours and haematologic malignancies. Importantly, constitutive activation of STAT proteins has been found in several leukaemias including acute myeloid leukaemia, acute promyelocytic leukaemia, acute lymphoblastic leukaemia, chronic myeloid leukaemia and chronic lymphocytic leukaemia (CLL). Constitutively activated STAT3 plays an important role in CLL biology. CLL cells harbour constitutive phosphorylation on S727 and acetylation on K685 and transient phosphorylation on Y705 residues. Moreover, STAT3 messenger RNA expression is significantly higher in CLL cells compared to healthy B-lymphocytes. Interestingly, STAT3 inhibition was disclosed as an important by-product of ibrutinib treatment in CLL patients.
The purpose of this review is to describe the consequences of STAT3 dysregulation in CLL cells. Here, we discuss aberrantly modified processes by STAT3 activation in CLL cells such as proliferation, apoptosis, B cell receptor signalling, cytokine secretion, immune checkpoint regulation, microRNA regulation, free fatty acid metabolism and electron transport chain in the mitochondria.
信号转导及转录激活因子（STAT）蛋白是细胞质转录因子，可传递细胞因子、激素和生长因子的信号。STAT蛋白控制包括存活、增殖和分化在内的基本细胞过程。STAT的不适当激活可能导致细胞转化和白血病发生。约70%的实体瘤和血液肿瘤表现出异常的STAT3表达和/或激活，突出了其在肿瘤发生中的重要作用。在几种实体瘤和血液系统恶性肿瘤中发现了异常的STAT3激活。重要的是，在包括急性髓系白血病、急性早幼粒细胞白血病、急性淋巴细胞白血病、慢性髓系白血病和慢性淋巴细胞白血病（CLL）在内的几种白血病中发现了STAT蛋白的组成性激活。组成性激活的STAT3在CLL生物学中起重要作用。CLL细胞在S727位点存在组成性磷酸化，在K685位点存在乙酰化，在Y705位点存在瞬时磷酸化。此外，与健康B淋巴细胞相比，CLL细胞中STAT3信使核糖核酸的表达显著更高。有趣的是，STAT3抑制被发现是CLL患者使用伊布替尼治疗的一个重要副产物。
本综述的目的是描述CLL细胞中STAT3失调的后果。在此，我们讨论CLL细胞中由STAT3激活引起的异常修饰过程，如增殖、凋亡、B细胞受体信号传导、细胞因子分泌、免疫检查点调节、微小核糖核酸调节、游离脂肪酸代谢和线粒体中的电子传递链。
