Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore 110974, Singapore.
Department of Pathology, National University Hospital, National University Health System, Singapore 110974, Singapore.
Int J Mol Sci. 2018 Jun 30;19(7):1931. doi: 10.3390/ijms19071931.
Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is an aggressive malignancy with a poor prognosis. While the introduction of L-asparaginase in the treatment of this disease has significantly improved the prognosis, the outcome of patients relapsing after asparaginase-based chemotherapy, which occurs in up to 50% of patients with disseminated disease, remains dismal. There is hence an urgent need for effective targeted therapy especially in the relapsed/refractory setting. Gene expression profiling studies have provided new perspectives on the molecular biology, ontogeny and classification of ENKTL and further identified dysregulated signaling pathways such as Janus associated kinase (/Signal Transducer and activation of transcription (JAK/STAT), Platelet derived growth factor (PDGF), Aurora Kinase and NF-κB, which are under evaluation as therapeutic targets. Copy number analyses have highlighted potential tumor suppressor genes such as PR Domain Zinc Finger Protein 1 (PRDM1) and protein tyrosine phosphatase kappa (PTPRK) while next generation sequencing studies have identified recurrently mutated genes in pro-survival and anti-apoptotic pathways. The discovery of epigenetic dysregulation and aberrant microRNA activity has broadened our understanding of the biology of ENKTL. Importantly, immunotherapy via Programmed Cell Death -1 (PD-1) and Programmed Cell Death Ligand1 (PD-L1) checkpoint signaling inhibition is emerging as an attractive therapeutic strategy in ENKTL. Herein, we present an overview of the molecular biology and genomic landscape of ENKTL with a focus on the most promising translational opportunities.
结外 NK/T 细胞淋巴瘤，鼻型（ENKTL）是一种侵袭性恶性肿瘤，预后不良。虽然在治疗这种疾病中引入 L-天冬酰胺酶显著改善了预后，但在多达 50%的播散性疾病患者中，基于天冬酰胺酶的化疗后复发的患者的结局仍然很差。因此，迫切需要有效的靶向治疗，尤其是在复发/难治性情况下。基因表达谱研究为 ENKTL 的分子生物学、发生和分类提供了新的视角，并进一步确定了失调的信号通路，如 Janus 相关激酶（/信号转导和转录激活因子（JAK/STAT）、血小板衍生生长因子（PDGF）、极光激酶和 NF-κB，这些通路正在作为治疗靶点进行评估。拷贝数分析强调了潜在的肿瘤抑制基因，如 PR 结构域锌指蛋白 1（PRDM1）和蛋白酪氨酸磷酸酶 kappa（PTPRK），而下一代测序研究则确定了在生存和抗凋亡途径中经常发生突变的基因。表观遗传失调和异常 microRNA 活性的发现拓宽了我们对 ENKTL 生物学的理解。重要的是，通过程序性细胞死亡-1（PD-1）和程序性细胞死亡配体 1（PD-L1）检查点信号抑制的免疫疗法正在成为 ENKTL 中一种有吸引力的治疗策略。在此，我们概述了 ENKTL 的分子生物学和基因组景观，重点介绍了最有前途的转化机会。
