ALCL, anaplastic large‐cell lymphomas; ENKTL, human T‐cell leukemia/lymphoma virus 1; HLA, human leukocyte antigen; HTLV1, human T‐cell lymphotropic virus type 1; MEITL, monomorphic epitheliotropic intestinal T‐cell lymphoma; PTCL, peripheral T‐cell lymphoma; PTCL‐NOS, peripheral T‐cell lymphoma not otherwise specified; Tfh, T follicular helper.
Although TET2, DNMT3A, and IDH2 mutations have in principle opposite effects on cytosine methylation levels, they all individually result in decreased 5hmC levels. Interestingly, compared with normal Tfh cells, 5hmC levels are decreased in AITL, and more generally in PTCL (with the exception of hepatosplenic T‐cell lymphoma [HSTL]), irrespective of the mutational status, suggesting that epigenetic dysregulation is a common feature of PTCLs [22]. However, the functional consequences of these changes in cytosine methylation/hydroxymethylation are still poorly understood and warrant further comprehensive studies.
Other epigenetic regulators preferentially involved in post‐translational modifications of histones are also the target of genetic alterations. For example, inactivating mutations and/or deletions of SETD2, a histone methyltransferase adding methyl groups on the lysine residue 36 of histone 3, are almost constant in monomorphic epitheliotropic intestinal T‐cell lymphoma (MEITL; > 90% of cases) [23] and are also frequent in HTCL (about 30% of cases) [24]. These inactivating mutations result in decreased H3K36me3 levels, a histone mark which is usually associated with active transcription. Alterations of the KMT2 family of genes (KMT2D and KMT2C), encoding methyltransferases involved in the methylation of H3K4, an important process regulating gene transcription, have been reported in PTCLs such as Sézary syndrome [13], ENKTL [25, 26], PTCL‐NOS [27] and breast implant‐associated ALCL, where they correlate with a loss of H3K4 mono‐ and trimethylation [28]. Recurrent mutations in other epigenetic modifiers such as CHD2, CREBBP, or EP300 have also been reported in various PTCLs.
Signaling Pathways
Epigenetic alterations are not sufficient per se to drive tumor transformation. Indeed, most patients with isolated TET2 or DNMT3A mutations in hematopoietic progenitors develop clonal hematopoiesis of indeterminate potential [29, 30], and will not further develop a clinical hematologic malignancy [29, 30]. Furthermore, transgenic mice models that inactivate TET2 or DNMT3A do not develop spontaneous lymphoid malignancies or they develop with a very low penetrance [31, 32]. Both observations suggest that disruption of an epigenetic regulator is not sufficient and requires “second‐hit” events, especially affecting the cell signaling to drive T‐cell lymphomagenesis.
In normal T cells, T‐cell receptor (TCR) engagement by a specific peptide presented by the major complex of histocompatibility, when associated with activation signals from co‐stimulatory pathways, activates the transmission of positive signals using several critical signaling pathways. These will result in proliferation, activation, and metabolism adaptation. The main co‐stimulatory receptors are CD28 and ICOS, whereas PD1 and CTLA4 are responsible for negative regulation. Activation of TCR signaling induces activation of calcium mobilization, RAS activation, resulting in mitogen‐activated protein kinase, nuclear factor kappa B (NF‐κB) and activator protein 1 (AP‐1) activation, and cytoskeletal reorganization [33].
Converging data support an important role of TCR signaling in T‐cell lymphomagenesis. First, a specific translocation [t(5,9)(q33;q22)] has been reported in some PTCLs, which leads to the generation of an abnormal ITK‐SYK fusion protein [34] and to the development of a PTCL with constitutively activated TCR signaling in a transgenic mice [35]. Interestingly, independently of SYK/ITK fusion, SYK overexpression appears common to many PTCLs [36]. Second, 50–70% of Tfh‐derived PTCLs harbor a mutation in RHOA encoding for the p.G17V substitution [4, 14, 37]. Although the expression of the RHOAG17V variant in T cells was associated with disruption of the classical functions of RHOA, it induced increased cell proliferation and invasiveness in in vitro models [14, 37]. These effects could be explained by a change in the interactome of RHOAG17V mutant, which binds VAV1, resulting in VAV1 phosphorylation and NFAT signaling activation, indicating that RHOA mutation could be a major player in T‐cell signaling activation [38]. The link between RHOAG17V mutation and VAV1 activation is reinforced by the observation that VAV1 activating mutations or translocations are mutually exclusive to RHOAG17V mutations [38]. Interestingly, mouse models combining TET2 loss with expression of the RHOAG17V mutant in T cells, especially when combined with TCR stimulation by immunization, develop AITL‐like disease, confirming the concept that combination of TET2 and RHOA mutations can drive Tfh PTCL oncogenesis [39, 40]. In addition, sparse mutations among other genes involved in proximal or distal TCR signaling, such as CD28, PLCG1, and PI3K elements, have been detected in 50% of patients with PTCL, resulting in increased cell activation and proliferation [41]. Furthermore, in addition to CD28 activating mutations, CD28‐ICOS or CD28‐CTLA4 fusions, resulting in CD28 signaling activation, are present in around 5% of PTCL, notably in Tfh‐derived PTCL [5].
Alterations in genes involved in TCR or co‐stimulation pathways are also found in other PTCL entities, especially cutaneous T‐cell lymphomas (CTCL), where PLCG1 mutations are frequent [42]. DUSP22, a gene found to be rearranged in around 30% of systemic and cutaneous ALK‐negative ALCL, is a tumor suppressor gene encoding a dual‐specificity phosphatase, which inhibits TCR signaling and growth and promotes apoptosis in experimental models [43]. Interestingly, DUSP22‐rearranged ALCLs lack activation of signal transducers and activators of transcription 3 (STAT3), in contrast to other ALCLs, but associates with recurrent mutations in the musculin (MSC) gene, which in turn drive expression of the CD30–IRF4–MYC axis and cell cycle progression [44]. PTEN anomalies, resulting in PI3K signaling activation are also described in a significant proportion of cases [45]. In ATLL, integrative genomic studies also demonstrated the presence of mutations altering the TCR and NF‐κB pathway, such as mutations in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4, and CCR7 [46].
The inactivation of inhibitory signals can also result in T‐cell activation. Recent progress in immunotherapy revealed that PD1 is a critical element for T‐cell inhibition. A mouse model revealed that PD1 inactivation, mostly by deletion of Pdcd1, the gene encoding for PD1, allowed for tumor transformation in T cells harboring the ITK‐SYK translocation [47]. PDCD1 deletions are found in several PTCLs, but especially CTCL [47]. This potential tumor suppressor role of PD1 in PTCL raises some questions regarding the use of PD1–PDL1 checkpoint inhibitors in PTCL, which are currently under investigation.
The Janus‐associated kinase (JAK)–STAT pathway is also pivotal for T‐cell regulation, as it is critical for the transmission of the signal from cell membrane receptors to the nucleus. Engagement of a type I or type II cytokine receptor by a cytokine or growth factor induces JAK transphosphorylation and subsequent recruitment, phosphorylation and dimerization of STAT proteins that will enter to the nucleus to activate gene expression. There are four members of the JAK family (JAK1, JAK2, JAK3 and TYK2) and seven