and low incidence of ATLL development in HTLV1‐infected individuals, it is postulated that other events are required for transformation, besides the role of HTLV1 infection itself, which is supported by its constant presence and the monoclonal integration of a single viral copy in the majority of cases. It is estimated that an asymptomatic HTLV1‐positive individual carries between 10e4 to 10e5 distinct clones of HTLV1‐infected T cells and each clone is distinguished by a unique site of integration of the provirus into the host genome [94]. Conversely, a single dominant clone is found among a background of hundreds of clones in patients with ATLL [95]. The proviral integration site of HTLV1 into the host genome is strongly biased toward certain transcription factor binding sites, notably STAT1, TP53, and HDAC6 [96].
Two viral proteins are implicated in oncogenesis: the transactivator protein (TAX) that is critical for T‐cell proliferation mainly via activation of NF‐κB and AP‐1 pathways, and is involved in tumor initiation; and the antisense gene product basic leucine zipper protein (HBZ) that may serve as a tumor promoter and play a role in tumor maintenance [97]. However, most neoplastic cells do not express oncogenic viral TAX, and only express HBZ. The other genomic events identified to drive disease pathogenesis include alterations altering in T‐cell receptor‐NF‐κB signaling, T‐cell trafficking (e.g. CCR4, CCR7), and immunosurveillance, as described above [46].
Epstein–Barr Virus
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].
Chronic Antigenic Stimulation
Chronic antigen stimulation resulting in chronic B‐cell receptor or TCR activation, can promote lymphomagenesis. This concept is supported by the observation of biases in the B‐cell receptor repertoire in B‐cell malignancies, but most importantly the observation of response or cure after Helicobacter pylori or HCV eradication in some B‐cell malignancies, such as marginal zone lymphomas of splenic or mucosa‐associated lymphoid tissue types.
A similar model could be transposed to EATL. This primary intestinal lymphoma occurs as a rare but classical complication of celiac disease. Patients with celiac disease are intolerant to gluten, and uncomplicated lesions regress with gluten eviction. However, gluten intolerance translates to the development of refractory sprue, ulcerative jejunal lesions and ultimately EATL, characterized by a clonal expansion of aberrant intraepithelial lymphocytes, with aggressive features and poor prognosis. Genetic alterations are found in these lymphomas, especially affecting the JAK–STAT pathway [54], and correlation between EATL occurrence and poor observance of a gluten‐free diet in patients with celiac disease suggests the role of the chronic antigenic stimulation induced by gluten [103].
More recently, increasing numbers of ALCL developing at the contact of textured breast implants have been reported. The disease presents most often with neoplastic T cells restricted to the seroma and/or the surface of the periprosthetic capsule (“in‐situ form”), and more rarely as a tumor mass within the capsule and the adjacent tissues (“infiltrative form”). While the infiltrative form of the disease can have an aggressive course and requires systemic chemotherapy, the in‐situ form usually regresses after capsulectomy. A model of lymphomagenesis induced by local inflammation and chronic antigenic stimulation is proposed. The resulting high levels of cytokines in the periprosthetic confined milieu could favor the expansion of cytotoxic cells, which would subsequently acquire somatic mutations. Several studies have identified recurrent mutations in epigenetic modifiers (KMT2C, KMT2D, CHD2, CREBBP) and JAK–STAT signaling (STAT3, JAK1, STAT5B) pathway) [28, 104]. The role of a bacteria, Ralstonia pickettii, in promoting inflammation, has been suspected, although this remains controversial [105].
Other Factors
Only few physical factors have been identified as underlying factors favoring T‐cell lymphoma development. Analyses of mutational signatures derived from whole genome sequencing revealed that enrichment in ultraviolet radiation‐induced signature in CTCL are, suggesting that ultraviolet radiation could contribute to CTCL [106].
The role of mutations in epigenetic regulators which occur at high frequency in hematopoietic progenitor cells (see section 2.2.1.1 Signaling Pathways) is still unclear. Beside changes in the gene expression levels induced by epigenetic alterations in the regulatory regions, these mutations could induce some genomic instability, subsequently favoring the acquisition of additional mutations that could drive the tumor transformation. It has been recently postulated that TET2, IDH2, and DNMT3A could induce some degrees of genomic instability by various pathway. Mutations in IDH1/2 could also result, via the production of the oncometabolite D‐2 hydroxyglutarate, in impaired DNA repair, which could have therapeutic consequences [107, 108]. Alterations in TET proteins could also increase DNA damage [109, 110].
Few predisposing factors of PTCL development have been identified in population studies. In addition to HLA‐DPB1 association with NKTCL which could explain geographic differences in NKTCL incidence (see above), a germline HAVCR2 mutation altering TIM‐3
