Epigenetic targets in B- and T-cell lymphomas: latest developments

Abstract

Non-Hodgkin's lymphomas (NHLs) comprise a diverse group of diseases, either of mature B-cell or of T-cell derivation, characterized by heterogeneous molecular features and clinical manifestations. While most of the patients are responsive to standard chemotherapy, immunotherapy, radiation and/or stem cell transplantation, relapsed and/or refractory cases still have a dismal outcome. Deep sequencing analysis have pointed out that epigenetic dysregulations, including mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases (DNMTs), are prevalent in both B- cell and T-cell lymphomas. Accordingly, over the past decade, a large number of epigenetic-modifying agents have been developed and introduced into the clinical management of these entities, and a few specific inhibitors have already been approved for clinical use. Here we summarize the main epigenetic alterations described in B- and T-NHL, that further supported the clinical development of a selected set of epidrugs in determined diseases, including inhibitors of DNMTs, histone deacetylases (HDACs), and extra-terminal domain proteins (bromodomain and extra-terminal motif; BETs). Finally, we highlight the most promising future directions of research in this area, explaining how bioinformatics approaches can help to identify new epigenetic targets in B- and T-cell lymphoid neoplasms.

Keywords: BET inhibitors; DNMT; EZH2; HAT; HDAC; bioinformatics; clinical testing; drug combination; epigenetics; non-Hodgkin’s lymphoma.

Figure 1.

B- and T-cell lymphomagenesis. (a) Emergence of the main subtypes of B-cell non-Hodgkin’s lymphoma (B-NHL). Naive B cells first participate in the formation of germinal centers (GCs) upon interacting with antigens. In the dark zone, centroblasts prolife and undergo somatic hypermutation (SMH), while in the light zone, centrocytes are sorted on B-cell receptor (BCR)-based affinity and undergo class switch recombination (CSR). GC cells are the normal counterparts of follicular lymphoma (FL), Burkitt’s lymphoma (BL), and diffuse large B-cell lymphoma (DLBCL) of GC subtype (GCB). DLBCL of the activated B-cell subtype (ABC) originates from post-GC cells, and multiple myeloma (MM) arises from differentiated plasma cells. Chronic lymphocytic leukemia (CLL) can originate from either naïve or differentiated memory B cells. Mantle cell (MCL) and marginal zone lymphoma (MZL) arise from B cells located in the mantle and marginal zone of lymphoid follicles, respectively. (b) Intrinsic or extrinsic factors may favor TCLs pathogenesis through immune evasion, alterations in T cell receptor (TCR) signaling pathways, activation of transcription factors and proto-oncogenes, that favor the emergence of different entities during T cell differentiation from the thymus to lymph nodes. AITL, angioimmunoblastic T-cell Lymphoma; ALCL-ALK+, anaplastic large cell lymphoma, ALK-positive; EATL, enteropathy-associated T-cell lymphoma; ENKL, extranodal natural killer/T-cell lymphoma; FTCL, follicular T-cell lymphoma; HTCL, hepatosplenic γδ T-cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T cell lymphoma; PTCL, peripheral T-cell lymphoma.

Figure 2.

Alterations of chromatin states in B- and T-cell lymphoma. (a) Loss-of-function mutations affecting epigenetic regulators such as the SET domain of the histone-lysine N-methyltransferase 2D (MLL2/KMT2D), CREB binding protein (CREBBP), and E1A binding protein 300 (EP300) genes, as well as activating mutations of the enhancer of zeste homolog 2 (EZH2) histone methyltransferase (HMT) gene and the overexpression of HDAC1/2/6 have been reported in B-cell lymphoma cases. (b) Genetic alterations in DNA methylation genes affect Tet methylcytosine dioxygenase 2 (TET2), DNA methyl transferase 3 A (DNMT3A) and isocitrate dehydrogenase 2 (IDH2), as well as in chromatin remodelers such as SETD2, SETD1B, INO80, ARID1B, ARID2, ARID5B, SMARCC1 and histone acetylation genes such as EP300/CREBBP are found in T-cell lymphoma.