de Mel Sanjay, Tan Joshua Zhi-Chien, Jeyasekharan Anand D, Chng Wee-Joo, Ng Siok-Bian
Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore.
Department of Medicine, National University Health System, Singapore, Singapore.
Front Pediatr. 2019 Jan 17;6:405. doi: 10.3389/fped.2018.00405. eCollection 2018.
Epstein Barr virus positive T/NK lymphoproliferative disorders (EBV-TNKLPD) comprise a spectrum of neoplasms ranging from cutaneous lymphoid proliferations to aggressive lymphomas. The spectrum includes extranodal NK/T-cell lymphoma (ENKTL), aggressive NK-cell leukemia, and a group of EBV-TNKLPDs affecting children which are poorly characterized in terms of their molecular biology. Gene and miRNA expression profiling has elucidated RNA abnormalities which impact on disease biology, classification, and treatment of EBV-TNKLPD. Pathways promoting proliferation, such as Janus associated kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) and nuclear factor kB, are upregulated in ENKTL while upregulation of survivin and deregulation of p53 inhibit apoptosis in both ENKTL and chronic active EBV infection (CAEBV). Importantly, immune evasion via the programmed cell death-1 and its ligand, PD-1/PD-L1 checkpoint pathway, has been demonstrated to play an important role in ENKTL. Other pathogenic mechanisms involve EBV genes, microRNA deregulation, and a variety of other oncogenic signaling pathways. The identification of EBV-positive Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) as a tumor with a distinct molecular signature and clinical characteristics highlights the important contribution of the knowledge derived from gene and miRNA expression profiling in disease classification. Novel therapeutic targets identified through the study of RNA abnormalities provide hope for patients with EBV-TNKLPD, which often has a poor prognosis. Immune checkpoint inhibition and JAK inhibition in particular have shown promise and are being evaluated in clinical trials. In this review, we provide an overview of the key transcriptomic aberrancies in EBV-TNKLPD and discuss their translational potential.
爱泼斯坦-巴尔病毒阳性T/NK淋巴细胞增殖性疾病（EBV-TNKLPD）包括一系列肿瘤，从皮肤淋巴样增殖到侵袭性淋巴瘤。这一谱系包括结外NK/T细胞淋巴瘤（ENKTL）、侵袭性NK细胞白血病，以及一组影响儿童的EBV-TNKLPD，其分子生物学特征尚不明确。基因和miRNA表达谱分析已阐明影响EBV-TNKLPD疾病生物学、分类和治疗的RNA异常。促进增殖的信号通路，如Janus相关激酶/信号转导子和转录激活子（JAK/STAT）以及核因子κB，在ENKTL中上调，而生存素的上调和p53的失调在ENKTL和慢性活动性EB病毒感染（CAEBV）中均抑制细胞凋亡。重要的是，通过程序性细胞死亡蛋白1及其配体PD-1/PD-L1检查点通路进行的免疫逃逸已被证明在ENKTL中起重要作用。其他致病机制涉及EBV基因、miRNA失调以及多种其他致癌信号通路。将EBV阳性的外周T细胞淋巴瘤，非特指型（PTCL-NOS）鉴定为具有独特分子特征和临床特征的数据突出了基因和miRNA表达谱分析在疾病分类中的重要贡献。通过对RNA异常的研究确定的新治疗靶点为预后通常较差的EBV-TNKLPD患者带来了希望。特别是免疫检查点抑制和JAK抑制已显示出前景，正在临床试验中进行评估。在本综述中，我们概述了EBV-TNKLPD中的关键转录组异常，并讨论了它们的转化潜力。
