The Peripheral T-Cell Lymphomas. Группа авторов
consequences of many of them are largely unknown, some events altering the noncoding region may have important biological consequences. For example, structural variants altering 3′ untranslated region (UTR) of PDL1 resulting in PDL1 overexpression and immune escape, have been described in adult T‐cell leukemia/lymphoma (ATLL) [9] or in extranodal NK/T‐cell lymphoma (ENKTL), nasal‐type [10], two diseases related to viral infections. Dysregulation of non‐coding RNA is also observed; some microRNA [11] or small nucleolar RNA [12] signatures are entity specific and could aid in diagnosis, while some may play a role in oncogenesis. However, the role of the anomalies affecting the non‐coding genome is largely unexplored.
Beyond the genetic and epigenetic anomalies, viruses can directly or indirectly play a role in the oncogenic transformation. Two viruses with oncogenic properties, human T‐cell lymphotropic virus type 1 (HTLV1) and Epstein–Barr virus (EBV) are causally linked to a spectrum of lymphoproliferations derived from T or NK cells (see below).
Deregulated Pathways in Peripheral T‐cell Lymphoma Oncogenesis (Figure 2.1, Table 2.1)
Epigenetic Regulation
Genomic studies have highlighted epigenetic regulators as the category of genes most frequently altered in PTCL. Indeed, integrated molecular analyses of Sézary syndrome [13], ATLL [10], or PTCL of T follicular helper (Tfh) origin [14, 15] has revealed anomalies in epigenetic regulators in up to 90% of the cases. For example, mutations in TET2 [14–16], DNMT3A [17] and IDH2 [18] are observed in 80%, 30%, and 20–30% of PTCL derived from Tfh cells, respectively. These three mutations induce changes in cytosine methylation and hydroxymethylation levels. TET2 is an α‐ketoglutarate‐dependent dioxygenase involved in the successive oxidation of 5‐methylcytosine to 5‐hydroxymethylcytosine (5hmC) to 5‐formylmethylcytosine and 5‐carboxymethylcytosine, resulting in the demethylation of 5‐cytosine, through the thymine DNA glycosylase‐mediated base excision system [19]. Although TET2 was initially thought to play an important role in active cytosine demethylation, evidence is emerging that TET2 is pivotal in the generation of 5hmC, which is critical for enhancer functions [20]. DNMT3A is a de novo DNA methyltransferase, supporting the transformation of 5‐cytosine to 5‐methylcytosine. Mutations in TET2 and DNMT3A are loss of function and distributed along the coding sequences of the genes, with few hotspots, like the dominant‐negative DNMT3AR882X mutant [20]. IDH2 mutations confer a neoenzymatic activity producing D‐2 hydroxyglutarate. This metabolite, often referred to as an oncometabolite, is physiologically present at very low levels, and inhibits numerous α‐ketoglutarate‐dependent dioxygenases, including TET proteins or histone demethylases [21]. While IDH1/2 and TET2 mutations in acute myeloid leukemia are mutually exclusive, both resulting in a specific methylation profile, they frequently coexist in AITL.
Figure 2.1 Summary of deregulated signaling pathways in peripheral T‐cell lymphoma. Orange boxes: lymphoma entities of the adaptive type; purple boxes: lymphoma entities of the innate type. ALCL, anaplastic large‐cell lymphoma; ALK, anaplastic lymphoma kinase; ATLL, adult T‐cell leukemia/lymphoma; CTCL, cutaneous T‐cell lymphoma; EATL, enteropathy‐associated T‐cell lymphoma; ENKTL: extranodal natural killer/T‐cell lymphoma; HSTL, hepatosplenic T‐cell lymphoma; JAK, Janus‐associated kinase; LGL, large granular lymphocyte leukemia; MEITL, monomorphic epitheliotropic T‐cell lymphoma; PTCL: peripheral T‐cell lymphoma; PTCL‐NOS, peripheral T cell not otherwise specified; STAT, signal transducers and activators of transcription; TCR, T‐cell receptor; TFH, T follicular helper cells.
Table 2.1 Main nodal and extranodal mature T‐cell neoplasms with summary of their main characteristics.
| Major mature T‐cell neoplasms | Postulated cell of origin | Main genetic features |
|---|---|---|
| Adaptive immune system | ||
| 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 |
| Cutaneous T‐cell lymphoma (Sézary syndrome, mycosis fungoides) | CD4 T‐cell | 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 |