been observed in AITL and occur with TET2 mutations.
DNMT3 loss of function is reported in 10–25% cases of AITL, 80% of which also have TET2 mutations confirming a strongly dysregulated epigenome in AITL. Epigenetic mutations in TET2, DNMT3, and IDH2 are strongly associated with the RHOA G17V mutation. The RHOA G17V mutation is seen exclusively in the background of TET2 mutations with or without IDH2 mutations in 70% of AITL patients. These mutants do not bind GTP and disrupt the important RhoA signaling. The RHOA G17V mutation results in increased AKT activity through several interactions that include VAV1, ROCK1 and 2 and PTEN. A subset of IDH2 mutated cases harbor both TET2 and RhoA [69].
Epigenetic therapies deserve a special mention for this subtype. Single‐agent use of the HDACi romidepsin and belinostat is approved for relapsed PTCL. As discussed above, epigenomic dysfunction in PTCL is quite extensive and seems to have the highest impact in AITL. Interestingly, romidepsin and belinostat have been reported to have an overall response rate of 30% [23] 45% in AITL in the pivotal trials, which is higher than reported for other TCLs [70, 71]. While some have interpreted these data to imply a greater level of vulnerability of AITL to HDAC inhibitor, the data should be viewed with caution given the very small numbers of this subset in those studies, and the absence of any randomized data for these drugs in this setting.
Similarly, HMA are only recently being evaluated in the treatment of AITL, given the preponderance of mutations affecting genome methylation in this particular subtype. Delarue et al. reported on the use of 5‐azacitidine in 19 patients with relapsed/refractory PTCL. Rituximab was added if the patients were positive for EBV. The overall response rate was 75% in the 12 patients with AITL compared with 15% for the other subtypes (limited only to PTCL‐NOS), with a complete response rate 42% among patients with AITL. Mutational analysis showed that all responding patients had a TET2 mutation [72]. Combinations of romidepsin and 5‐azacitadine have reported even higher response rates of 83% with a complete response of 50% among all patients with PTCL, and an even higher overall response rate among patients with AITL [52]. This combination is now being tested in a larger study with correlatives to study possible biomarkers that may predict response in the future. Other strategies being explored include inhibitors of IDH2 specific for the R172 codon and PI3K inhibitors.
Anaplastic Large‐cell Lymphoma
ALCL is characterized by sheets of CD30 positive anaplastic large cells. Systemic ALK‐negative ALCL nodal lymphomas have all the other morphological and phenotypical features of a CD30 positive cytotoxic ALCL except ALK expression [73]. DNMT3 and TET2 mutations have been identified in some cases, albeit comparatively few compared with AITL and PTCL‐Tfh [74].
Adult T‐cell Leukemia/Lymphoma
Methylation pathway genes (TET2, DNMT3, and IDH2) are altered in ATLL, albeit to a far less extent than in AITL. Polycomb‐dependent repression is enhanced in ATLL by trimethylation of histone lysine 27 and affects half the genes in ATLL. EZH2 and other components of the PRC2 complex are upregulated in ATLL. This biology suggests that EZH2 inhibitors may have a potential role in this particular subtype. While to date this experience is limited, pharmacologic inhibition of EZH2 results in apoptosis of ATLL cells. The genes that are commonly affected include several tumor‐suppressor genes like BCL2L11 (BIM), and CDKN1A and CD7. KDM6B, a gene that encodes a lysine‐specific demethylase that specifically demethylates di‐ or tri‐methylated lysine 27 of histone H3 is considered a repressive histone mark controlling chromatin condensation. The gene is downregulated in ATLL, thus locking in the effects initiated by Tax even when Tax expression is lost during disease progression [75].
Intestinal T‐cell Lymphoma
These rare lymphomas are derived from intestinal intraepithelial lymphocytes and express the mucosal homing receptor CD103. There are at least three clinical pathologic variants. The two aggressive variants are now called enteropathy‐associated and monomorphic epitheliotropic intestinal TCL. The third subtype, indolent T‐cell lymphoproliferative disorder of the gastrointestinal tract has a more indolent course [76]. The majority of cases are of the γδ subtype, while about one‐third of cases have the STAT5B mutation similar to hepatosplenic TCL (HSCTL). The Janus‐associated kinase/ signal transducers and activators of transcription (JAK/STAT) pathway is the most frequently mutated pathway with frequent mutations in STAT5, JAK1, JAK2, STAT3, and SOC1, as well as less common mutations in KRAS, TP53, TERT11.
SETD2 is the most frequently mutated gene in enteropathy‐associated TCL (32% of cases) [60]. The SETD2 gene encodes a histone methyltransferase that is specific for lysine‐36 of H3, which has been associated with transcriptional activation. SET domain containing 2 (SETD2) is an enzyme that in humans is encoded by the SETD2 gene. SETD2 protein is a histone methyltransferase that is specific for lysine‐36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. The trimethylation of lysine‐36 of histone H3 is required in human cells for homologous recombinational repair and genome stability. Depletion of SETD2 increases the frequency of deletion mutations that arise by the alternative DNA repair process of microhomology‐mediated end joining [77]. While SETD2 is mutated in about one‐third of TCL cases, it is likely to be identified in other subtypes of PTCL.
Hepatosplenic T‐cell Lymphomas
This rare entity is derived from gamma/delta T‐cells which occurs more commonly in young men with a median age of around 35 years [76]. The malignant cells may be negative for both CD4 and CD8, and may infiltrate the liver, spleen, and bone marrow in a marked sinusoidal pattern. Recurrent isochromosome 7q and trisomy 8 has also been noted on cytogenetic studies, while. STAT5B is mutated in up to 31% of cases, STAT3 in 9% and PI3KCD in 9% [78]. Interestingly, gene‐expression profiling studies have confirmed that tends to cluster close to the extranodal natural‐killer (NK)/TCL (ENKTCL) with overexpression of NK markers like KIR and killer lectin‐like receptors, CD16, CD56, and NKG2F especially in the T γδ as opposed to αβ subtypes [60].
Dysregulation of various epigenetic pathways, some seen in other subtypes, others of which appear more commonly in HSTCL. For example, comprehensive genomic studies of HSTCL have identified chromatic modifying gene mutations in a variety of genes including SETD2 and ARID1B in up to 62% of cases. The ARID1B gene (AT‐rich interactive domain‐containing protein 1B) encodes for a protein that binds to DNA helping to target SWI/SNF complexes which regulate gene expression by modulating chomatin remodeling. Somatic mutations in ARID1B are associated with many malignancies, consistent with its functions as a tumor suppressor gene [79–82].
Extranodal Natural Killer/T‐cell Lymphoma
These rare lymphomas arise from NK/T cells and are typically divided into three different subtypes: ENKTL, aggressive NK‐cell leukemia (NKCL), and chronic lymphoproliferative disorder of NK cells.
Genome‐wide studies have shown that there is global hypermethylation in ENKTCL, and that several important genes including TP53, SHP1, and TP73 are affected. TP73 is a TP53 family member which may also be a negative regulator of NK‐cell activation. SHP1 regulates STAT3 activation and its loss may contribute to the aberrant activation of the JAK–STAT3 pathway. Other important genes that are inactivated by this are the proapoptotic BIM, DDX3X, and DAPK1. There is frequent methylation of ASNS, which encodes asparaginase synthetase and may explain the sensitivity of ENKTCL to L‐asparaginase therapy. Whole exome sequencing has described the mutational landscape of ENKTCL. Most frequent
