Читать книгу The Peripheral T-Cell Lymphomas - Группа авторов - Страница 38

EBV, also known as HHV4 (human herpesvirus type 4), is found in approximately 95% of the adult population worldwide. B cells are the main target of EBV infection but EBV can also infect epithelial cells, mainly in the nasopharyngeal region, which is thought to occur during viral reactivation. In line with its capacity to infect epithelial cells and B cells, EBV is associated with nasopharyngeal carcinoma and several B‐cell malignancies, notably endemic Burkitt lymphoma and B‐cell lymphoproliferative disorders in immunosuppressed patients. EBV infection is also considered as a sine qua none characteristic of ENKTL and aggressive NK‐cell leukemia as well as in other rare disorders such as systemic EBV+ T‐lymph or hydroa vacciniforme‐like lymphoproliferative disorder, two diseases occurring mainly in children and adolescents from Asia and Central and South America.

In addition to these EBV‐positive T‐cell neoplasms where EBV genome is found in virtually all neoplastic cells, in other instances, notably Tfh lymphomas, EBV may be detected in a smaller subset of the tumor cells corresponding to reactive B cells. In ENKTL, the tumor most commonly occurs in sites of primary EBV infection. Since T and NK cells do not normally harbor CD21 which is the membrane receptor mediating EBV entry into the cells, the mechanism proposed is the infection of resident NK (or T) after acquisition of CD21 through “trogocytosis” or via the direct transfer of viral episomes [98, 99].

In ENKTL, like in most EBV‐associated malignancies, EBV infection expresses a type II latency program, which comprises several latent proteins (LMP1, EBNA, and LMP2). The latent protein best characterized with respect to oncogenic properties is LMP1, a signaling protein that imitates a constitutively active tumor necrosis factor receptor, and activates mitogen‐activated protein kinases and STAT and NF‐κB transcription factors in B cells [100]. LMP1 increases proliferation and survival of the infected cells. Similarly, while a role for EBV in ENKTL pathogenesis is highly suspected, its precise oncogenic functions in NK and T cells are not fully deciphered. An enrichment of the NF‐κB pathway is observed in ENKTL and activated EBV‐infected NK cells, and produce IL2 and IL9, which are two cytokines important for NK cell activation and proliferation.

The immunosuppressive background in ENKTL, due notably to IL10, may promote tumor expansion as well as expression of the oncogenic protein LMP1 [52]. The proliferating EBV‐infected NK cells might first manifest as a chronic active EBV infection. During their expansion, they further acquire other genomic alterations such as mutations, involving RNA helicases (DDX3X), tumor suppressors (TP53), JAK–STAT pathway molecules (JAK3, STAT3, STAT5B), and epigenetic modifiers (MLL2, ARID1A, EP300, and ASXL3), as well as constitutive activation of growth factors and/or transcription factors, ultimately resulting in a full blown ENKTL. Additionally, genome‐wide association studies have identified a significant association to constitutive genetic variants like HLA‐DPB1 on 6p21.3, and IL18RAP on 2q12.1 indicating baseline susceptibility of certain individuals for the development of ENKTL [101, 102].