EBV and the Pathogenesis of NK/T Cell Lymphoma

SIMPLE SUMMARY: Extranodal NK/T cell lymphoma (ENKTCL) is an aggressive lymphoma associated with Epstein-Barr virus (EBV) infection that occurs mainly in Asian and Latin American populations. In the last decade, the genetic landscape of ENKTCL has been characterized comprehensively using next-generation sequencing (NGS). This and similar high-throughput approaches revealed that these lymphomas are distinguished by frequent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. This review aims to provide a comprehensive overview about the role of EBV infection and a comparison of the EBV strains and LMP1 variants among different populations. Moreover, a brief summary of the ENKTCL genetic landscape is presented, highlighting the main therapeutically targetable pathways in ENKTCL oncogenesis: the JAK-STAT signaling pathway, the immune response evasion, MYC overexpression, as well as epigenetic alterations. ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. The genomic landscape in ENKTCL highlights mechanisms of lymphomagenesis, such as immune response evasion, secondary to alterations in signaling pathways or epigenetics that directly or indirectly interfere with oncogenes or tumor suppressor genes. This overview discusses the most important findings of EBV pathogenesis and genetics in ENKTCL.