Lymphoma of mature Tfh cells:AITLFollicular T‐cell lymphomaNodal PTCL with Tfh phenotype
Tfh cell subset
Epigenetic: mutations in TET2 (~80%), DNMT3A (~30%), IDH2R172 (20–30%) Signaling: mutations in RHOAG1V (50–70%), CD28, PLCG1, (5–15% each), VAV1; fusions: ITK‐SYK (follicular T‐cell lymphomas), ICOS‐CD28, ICOS‐CTLA4, VAV1‐STAP2 Other: rare TP53 anomalies Abundant microenvironment encompassing stromal and reactive cells Virus: Epstein–Barr virus in B cells
ALCL, ALK‐positive
Activated cytotoxic T cells
Signaling: ALK fusion resulting from t(2;5)(~ 80% cases) or t(2;X) (~20%) involving NPM or another partner gene, respectively, and consequently STAT3 activation
ALCL, ALK‐negative
Activated cytotoxic T cells
Epigenetic: mutations in KMT2 family genes (especially in breast implant‐associated ALCL) Signaling:DUSP22 rearrangement (30%), frequently associated with MSCE116K mutation and lack of STAT3 activationMutations in JAK1, STAT3 (20%), fusions involving ROS1, TYK2, or FRK, all resulting in STAT3 activation Other: TP63 rearrangement (2–8%)
PTCL‐NOS
Activated mature T cell, mostly CD4+ central memory type of the adaptive immune system; include Th1 and Th2 cell subsets
Molecular subsets defined on the basis of gene expression signatures and expression of Th1 (TBX21) vs. Th2 (GATA3) transcription factors, may be clinically relevant:PTCL‐TBX21 enriched in mutations in DNA methylatorsPTCL‐GATA3 with frequent loss/mutations in tumor suppressors (CDKN2A/B‐TP53 and PTEN/PI3K pathways)
Adult T‐cell leukemia/lymphoma
T –cells, usually CD4, with a regulatory phenotype
Epigenetic: mutations in TET2 (10%), EP300 and others Signaling: mutations in PLCG1 (30%), PRKCB, CARD11, other NFκB genes, mutations in RHOA, activating NOTCH1 mutations Immune surveillance: mutations in HLA, beta 2 microglobulin or CD58, structural variants involving PDL1 3′ untranslated region Others: alterations in TP53, CDKN2A Virus: clonal integration of HTLV1, resulting in expression of TAX and HBZ oncogenic viral proteins during the initiation or maintenance of the tumor
Epigenetic: multiple mutations, the most frequent being ARIDIA Signaling: mutations in; PLCG1, PTEN, CARD11, fusions involving ICOS‐CD28 or CTLA4, alterations inTNFRSF1B Other: CDKN2A deletion, mutation/deletion in TP53
Innate immune system
ENKTL, nasal type
Activated NK cell (> 70%) > Tγδ or Tαβ cytotoxic cell
Epigenetic: mutations in BCOR, KMT2D, TET2 ARID1A, EP300 and ASXL3 Signaling: mutations in STAT3, STAT5B, JAK3 Immune surveillance: structural variants involving PDL1 3′ untranslated region Others: mutations in DDX3X, TP53 Virus: EBV constantly present in neoplastic cells (latency II) Association to constitutive genetic HLA‐DPB1 variants
Enteropathy‐associated T‐cell lymphoma
Intestinal intraepithelial T lymphocyte (Tαβ > Tγδ)
Epigenetic: mutations in TET2, SETD2 (uncommon) Signaling: mutations in JAK1, JAK3, STAT3, RAS Others: alterations in TP53 HLA association: DQ2‐DQ7 Frequent gains in 9q31.3 Association with celiac disease (gluten intolerance)
MEITL
Intestinal intraepithelial T lymphocyte (Tγδ > Tαβ)
Epigenetic: mutations and/or deletions in SETD2 (> 90%) Signaling: mutations in STAT5B, more rarely JAK3 Others: alterations in TP53 No reported HLA association Lack of association to celiac disease
Hepatosplenic T‐cell lymphoma
Tγδ > > Tαβ cytotoxic cell of the innate immune system
isochromosome 7q (~ 60–70%) Epigenetic: mutations in SETD2 (~ 40%) Signaling: mutations in STAT5B (~ 30%), STAT3 (10%)
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,
mature T‐cell neoplasms
