reduce RNA helicase activity but its role in pathogenesis is unclear. This study also confirmed the mutations in TP53 and STAT3 as well as mutations that affect epigenetic modifiers [83]. FAS is mutated or deleted in ENKTCL. There is upregulation of BCLXL and BCL2 through STAT3 or STAT5 activation which, together with the inactivation of BIM, may represent mechanisms of apoptosis resistance in ENKTCL. The interaction of the activated STAT3 pathway and the cytokine milieu promotes tumorigenesis. There are frequent mutations noted in STAT3 itself affecting the SH2 domain that prolong the activation of STAT3 even when cytokine concentrations are suboptimal. These mutations also lead to increased secretion of cytokines like IL‐10 and vascular endothelial growth factor, which promote the immunosuppressive tumor microenvironment. JAK3 mutations have also been noted in ENKTCL that drive STAT3 and can be inhibited by JAK inhibitors [83].
Mycosis Fungoides and Sézary Syndrome
A number of studies have published data that define the genomic landscape of Sézary syndrome [2–4, 79, 80, 84, 85]. The Leiden group [81] identified 126 recurrent genes with hypermethylation of CpG‐rich promoters as candidates for transcriptional repression which may play a potential causal role in the pathogenesis of the syndrome. Their results show aberrant DNA methylation patterns in CD4‐enriched T cells from peripheral blood samples, patterns that are distinct from those of patients with inflammatory erythroderma and from healthy volunteers. Whereas 7.8% of 473 921 CpG sites were hypomethylated, 3.2% showed marked enrichment and selection for hypermethylated CpG sites within the proximal region of gene promoters, including some genes that have previously been shown to be hypermethylated in CTCL.
A comparison with the Cancer Genome Atlas network data of solid tumors showed that the prevalence of methylation abnormalities is significantly higher in Sézary syndrome, suggesting that DNA methylation plays a critical role in the pathogenesis of this T‐cell malignancy [82]. Hypermethylation of a series of genes appeared to distinguish Sézary syndrome from inflammatory erythrodermas, notably involving methylation of the CMTM2 gene, which encodes a chemokine‐like factor expressed in testis, bone marrow, and peripheral blood cells, was appeared restricted to Sézary syndrome. Interestingly, some of the highly expressed genes identified in Sézary syndrome, such as those for CD158 (KIR3DL2), DNMT3, PLS3, and TWIST1, have large CpG islands, suggesting that loss of methylation may be a mechanism for the activation of these genes; some are structural genes, which are not normally expressed in T cells, nor immune cells such as PLS3 (the T‐plastin gene) and DNMT3 [86]. The increased expression of these genes has been observed repeatedly in Sézary syndrome by different groups, using multiple platforms to analyze gene expression. Expression of these genes is not seen in other hematologic malignancies, suggesting a specific altered regulatory pathway in mycosis fungoides/Sézary syndrome that can reveal markers used for diagnosis and potentially targeting the cells in treatment. That these genes are turned on in Sézary syndrome with detectable frequency is unique to mycosis fungoides/Sézary syndrome and indicates definable a pathologic mechanism that befalls mature CD4+ T cells, which leads to mycosis fungoides/Sézary syndrome. To what degree the demethylation of genes is important in the development of mycosis fungoides/Sézary syndrome remains unclear. However, supporting the role of epigenetics in mycosis fungoides/Sézary syndrome, the T‐plastin (PLS3) gene has been shown to be hypomethylated at CpGs [87].
Moreover, gain of function mutations of DNMT3A have been identified in Sézary syndrome [2–5]. Next‐generation sequencing studies have already highlighted that C‐to‐T mutations are among the most frequent signature detected in Sézary syndrome, and this might reflect spontaneous deamination of methylated cytosines [3–5].
TET loss‐of‐function mutations are now recognized as one of the most frequent early genetic abnormalities in hematologic malignancies, including TCL and Sézary syndrome [3–5, 84, 85]. Furthermore, a constellation of mutations in mature T‐cell malignancies, including Sézary syndrome, appear to show selection for genes involved in regulating epigenetic modifications, including IDHs, which inhibit TET proteins; ARID1A/B, which form part of chromatin modeling complexes; and MLL genes, which mediate histone methyltransferases [2, 4, 5, 84].
Established and Emerging Drugs Targeting the T‐cell Lymphoma Epigenome
As shared in other chapters, there are a number of new drugs that target the PTCL epigenome which have been approved by various regulatory agencies around the world. A summary of these data is provided in Table 3.2. In addition to the approved agents, there are a number of promising single‐agent drugs that target the epigenome in unique fashion, which may play an important role, alone or in combination, in the treatment of T‐cell malignancies. A review of these novel agents is shared below.
DNA Methyltransferase Inhibitors
As discussed previously, a host of mutations in genes governing DNA methylation suggests that another class of drugs targeting the epigenome, namely the HMA, can play a crucial role in the development of novel therapeutic strategies. The DNMT inhibitors (or HMA as they are commonly termed) including azacitidine and decitabine, for example, represent the first class of epigenetic modulating drugs to be approved by the Federal Drug Administration (FDA). These drugs are pyrimidine nucleoside analogues of cytosine that have the ability to become incorporated into DNA and form covalent bonds between the 5‐azacytosine ring and the DNMT enzyme, thus causing irreversible DNMT inactivation [92]. Logically, DNMT inhibitors would seem likely to function by reversing the silencing of tumor‐suppressor genes, although the precise mechanism of action of DNMT inhibitors is poorly understood. While this phenotype of increased CpG methylation is a well‐established and a recurrent pathological feature across many types of cancer, mutations in important genes governing DNA methylation leading to a hypermethylated phenotype in PTCL suggest that drugs such as 5‐azacitidine and decitabine can be an important component of future combination regimens in select subtypes of these diseases. In ATLL, an in vitro study revealed that 5‐azacitidine inhibits growth of tumor cells by demethylation of the promotor region of a tumor suppressor and inhibition of the cyclin dependent kinase, p16INK4a [93]. In a study published by Delarue et al., injectable 5‐azacitidine, as a single agent, produced an overall response rate of 53% in 19 patients with relapsed or refractory PTCL [72]. Of the 19 patients in this study, 12 had a diagnosis of AITL and, in this patient population, the overall response rate was as high as 75% (9/12), with a complete response rate of 50% [94]. Interestingly, all the patients with AITL harbored TET2 mutations, with 58% harboring two mutations. In addition, 33% patients had DNMT3A mutations, 41% had RHOA mutations, with most of them having pG17V substitution. The impact of the mutation status on response was not evaluable as all the patients had the mutation [72]. Interesting, a recent report demonstrated a durable response to azacitidine in the absence of any identifiable mutations [95].
Table 3.2 Single agents targeting the T‐cell lymphoma epigenome.
| Drug | Class/Mechanism | Disease | Patients (n) | ORR (%) | CR (%) | Median PFS (months) | Median DOR (months) | Refs. |
|---|---|---|---|---|---|---|---|---|
| Romidepsin | Bicyclic pan‐HDACi | PTCL/CTCL | 130 | 25 | 15 | 4 | 28 | [88] |
| Vorinostat |
Hydroxamic acid‐based pan‐HDACi
|
