PTCL. Mutations in EZH2 have been shown to produce transcriptional silencing, leading to lymphomagenesis; inhibition of EZH2 of PTCL lines has induced marked cell growth arrest via marked upregulation of genes involved in cell cycle [10, 51, 53] In primary cutaneous ALCL (C‐ALCL), EZH2 mutations repress antitumor immunity via suppression of the C‐X‐C motif chemokine ligand 10/receptor 3 axis, which is important in T‐cell migration in inflammatory conditions, including PTCL [53].
Another example of an epigenetic lesion that may contribute to PTCL pathogenesis is KMT2D (also known as MLL2) [3, 51]. KMT2D encodes histone H3K4 methyltransferase. Mutations in this gene have been seen in 42% of PTCL in general, with approximately 25 and 36% of patients with the AITL and PTCL‐NOS subtypes carrying the mutation [54]. Figure 3.1 shows common epigenetic mutations, targets, and the drugs that can modulate this biology (Figure 3.2).
In addition to mutations in genes directly effecting epigenetic processes, TCLs commonly have mutations in pathways that can directly or indirectly affect this biology. For example, a gene found to be commonly mutated in PTCL is RHOA. While RHOA is not thought to be involved in maintaining the PTCL epigenome, it does belong to the Rho family of small GTPases, a group of Ras‐like proteins involved in intracellular signaling. Gain of function mutations in RHOA are seen in 50–70% of AITL compared with 15% in ATLL (with its own unique distribution of mutations) and are associated with cell proliferation and invasiveness [8, 35, 43]. In patients with AITL, 70% of cases are associated with a specific mutation in RHOA G17V, which appears to be correlate with paraneoplastic autoimmunity and lymphopenia [8, 55]. Preclinical models have shown that mice with a TET2 mutation as the initiating event and RHOA G17V mutation as the second hit develop TCLs with histologic and immunophenotypic features of AITL [35, 55–57]. Murine lymphoma models have shown that RHOA G17V leads to a reduced threshold for T‐cell receptor activation and can augment the PI3K‐AKT‐mTOR signaling signature [56]. In these murine models, treatment with duvelisib, the PI3K inhibitor, can produce significant reductions in tumor burden, while treatment with everolimus improved survival. This mouse model confirms that these mutations are pathogenic and provide rationale for interrogation of drugs targeting the epigenome as a therapeutic target in PTCL.
Figure 3.1 Common epigenetic targets in peripheral T‐cell lymphoma. TET = ten eleven translocation protein, 2HG = 2‐hydroxyglutarate, IDH2 = isocitrate dehydrogenase 2, 5hmC = 5‐hydroxymethylcytosine, EED = embryonic ectoderm development, SUZ12 = suppressor of zeste 12, EZH2 = enhancer of zeste 2, PCR2 = polycomb repressive complex 2, K27me3 = trimethylation at lysine 27 of histone 3 (aka H3K27me3), HDAC = histone deacetylase.
In addition to the importance of epigenetic mutations in PTCL lymphomagenesis, and the therapeutic rationale, recent evidence suggests that surveillance of these mutations may be useful in the monitoring of TCL response to therapy. Cell‐free DNA (cfDNA) is increasingly being validated for the purpose of detection of minimal residual disease, as well as for the genetic profiling of a known malignancy. Mutations in genes with established roles in epigenetic regulation such as TET2, DNMT3A, and IDH2 have been found to be 83% concordant between cfDNA and tissue biopsy samples in patients with AITL, and may emerge as a potential marker for detecting minimal residual disease [58].
Epigenetic Changes Within Specific T‐cell Lymphoma Subtypes
PTCL oncogenesis is a complex process thought to comprise two distinct components: one involving the dysregulation of T‐cell receptor signaling pathways intrinsic to malignant T cells, the other involving the interplay between the malignant cell and the non‐neoplastic tumor microenvironment. In addition, in select PTCL subtypes, the neoplastic transformation can be driven by viruses and chronic inflammation. In addition to the extensive epigenetic dysregulation discussed above, it is now becoming clear that a host of other molecular derangements can contribute to dysregulation of the PTCL epigenome, including but not necessarily limited to chromosomal translocations, insertions, deletions, point mutations, can result in unique fusion proteins, constitutive activation of driver pathways and gene loss [59, 60].
Figure 3.2 A simplified schematic of the action of histone deacetylase inhibitor.
Peripheral T‐cell Lymphoma Not Otherwise Specified
Epigenetic mutations are less frequent in PTCL‐NOS than in AITL (see section 3.3.2). There are reports of mutations in epigenetic regulators including KDM6A, MLL2, TET2, and DNMT3 which control genes involved in various signaling pathways including ZAP70, CHD8, APC, and TRAF3. Most importantly, a subgroup of PTCL is now defined as PTCL with T follicular helper (Tfh) cell phenotype (see below) and is now a separate category to PTCL‐NOS as defined by the World Health Organization classification.
Angioimmunoblastic T‐cell Lymphoma and Peripheral T‐cell Lymphoma with T Follicular Helper Phenotype
The clinical presentation of these two subtypes is nodal with a plethora of associated symptoms including arthralgias, skin rashes and autoimmune phenomena that can be explained by the role of Tfh cells in the regulation of B cells. The role of the Epstein–Barr virus (EBV) in the pathogenesis of AITL is still not defined but progression to EBV positive DLBCL is a well‐recognized occurrence in AITL [61]. The Tfh cell is the putative cell of origin for these two subtypes of PTCL. Normal Tfh cells are located in the germinal center of the lymph nodes, driven there by CXCR5 expression where they push germinal center B cells toward differentiation into plasma cells and memory cells. The two histological subtypes are distinguished by the presence (AITL) or absence (PTCL with Tfh phenotype) of abundant endothelial venules in the tumor sample. Both subtypes require that the neoplastic cells express at least two or more markers of Tfh cells such as PD‐1, BCL‐6, CXCL13, CD10, ICOS, and CXCR51 [62]. EBV‐infected cells are present in many cases of AITL. Higher EBV viral loads in tissues have been found to correlate with progression of disease and B‐cell clonality. Human herpesvirus 6B is also detected by PCR in almost half the cases of AITL. These viral infections reflect the immune deregulation seen in patients with AITL [63]. The most common cytogenetic abnormalities are trisomy 3, trisomy 7 and an additional X chromosome. Other genetic abnormalities include recurrent trisomy 5 often concurring with trisomy 21 [64]. Gene expression profiling of AITL identifies a pathogenic pathway that includes nuclear factor kappa B (NF‐κB signaling, interleukin 6 signaling, and transforming growth factor beta pathways and can be differentiated from PTCL‐NOS [60]. Small focal deletions show enrichment in genes resulting in dysregulation of the PI3K‐AKT‐mTOR pathway, similar to that demonstrated in the murine models discussed above. Half of AITL‐ and TFH‐derived PTCLs have mutations in the T‐cell receptor signaling pathways, including of CD28, FYN, PLCG1, CARD11, PI3K, CTNNB1, and GTF21 [8, 60, 65–68].
These two subtypes exhibit the highest degree of epigenetic dysregulation within the PTCL subgroup and may be the most susceptible to epigenetic therapies [34, 42]. Mutations in IDH1 and IDH2, which encode cytosolic and mitochondrial forms of IDH, lead to loss of normal catalytic activity as well as production of 2‐hydroxyglutarate. Downstream effects include inhibition of the TET family of DNA hydrolases resulting in abnormal histone and DNA methylation that leads to T‐cell transformation. IDH2 mutations are identified in about a third of AITL cases and some cases of PTCL. TET2 inactivating missense or nonsense mutations or insertions/deletions have been reported in up to 85% of AITL resulting in DNA hypermethylation, which also appears to have
