The role of epigenetics in T-cell lymphoma

Abstract

Malignant lymphomas are a group of diseases with epigenomic abnormalities fundamental to pathogenesis and pathophysiology. They are characterized by a high frequency of abnormalities related to DNA methylation regulators (DNMT3A, TET2, IDH2, etc.) and histone modifiers (EZH2, HDAC, KMT2D/MLL2, CREBBP, EP300, etc.). These epigenomic abnormalities directly amplify malignant clones. They also originate from a hematopoietic stem cell-derived cell lineage triggered by epigenomic changes. These characteristics are linked to their high affinity for epigenomic therapies. Hematology has led disease epigenetics in the areas of basic research, clinical research, and drug discovery. However, epigenomic regulation is generally recognized as a complex system, and gaps exist between basic and clinical research. To provide an overview of the status and importance of epigenomic abnormalities in malignant lymphoma, this review first summarizes the concept and essential importance of the epigenome, then outlines the current status and future outlook of epigenomic abnormalities in malignant lymphomas.

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

“…Deregulated expression and/or activity of these epigenetic writers, lead to genome-wide DNA and histone modification pattern alterations, modifying the chromatin structure, and thereby leading to cancer development. 56 Importantly, HDACs have become a promising therapeutic targets (see below) in the context of some TCLs such as CTCL, through their role in the silencing of different BCL-2 proapoptotic family members and in the regulation of autophagy. 57 (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.…”

“…Deregulated expression and/or activity of these epigenetic writers, lead to genome-wide DNA and histone modification pattern alterations, modifying the chromatin structure, and thereby leading to cancer development. 56…”

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment

“…The TME is the main source of extrinsic growth, and the survival signal provided by the TME’s non-neoplastic cells including different hematopoietic (myeloid, lymphoid) and non-hematopoietic cells is essential for T-lymphoma survival ( 35 – 37 ) ( Figure 1 ). The source T-cell variant from which the tumorigenic T cell derives significantly dictates the composition of the TME ( 39 , 42 , 53 , 54 ). As in the case of AITL (angio-immunoblastic T-cell lymphoma), the overexpression of follicular T helper cells (Tfh) associated with cell surface receptors (ICOS, PD-1, and CXCR-5) along with BCL-6 established that AITL tumorigenic cells originated from Tfh cells.…”

“…These observations suggested that the cell of origin is a major factor behind the composition of the TME in developing T-cell lymphomas and established the importance of TCR-mediated signaling aided by co-stimulatory and cytokine signaling in transcriptional and posttranscriptional regulations of these master transcription factors ( 38 ). These signaling alternations subsequently result in the development of a specific TME, which is evident by the homology between the receptor profile of T-lymphoma cells and the T cells’ source of origin subtypes ( 53 , 54 ). Subsequently, the constituents of the TME in turn influence the availability of ligands and cytokines which drive the T-cell lymphoma growth proliferation and survival.…”

Therapeutic challenges in peripheral T-cell lymphoma

“…Disruption of DNA methylation and histone modifications has become a hallmark of these diseases and the basis for epigenetically targeted therapies [ 88 ]. As the understanding of epigenetic complexity continues to deepen, it has been found that mutations in these epigenetic regulators have a global impact on lymphoma development and drug sensitivity, and the ability to silence multiple genes at the same time through the regulation of a large number of genes leads to polygenic drug resistance [ 89 , 90 ].…”