Targeting epigenetic regulators in the treatment of T-cell lymphoma

Ahmed, Nada; Feldman, Andrew L.

doi:10.1080/17474086.2020.1711732

Cited by 8 publications

(8 citation statements)

References 136 publications

(157 reference statements)

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“…Epigenetic modulations, such as histone modification and DNA methylation, have been observed in TCL [ 55 ]; however, epigenetic modulation of EBV proteins and microRNAs on TCL remains largely unknown [ 56 ] and, therefore, requires extensive research.…”

Section: Ebv Associated Malignanciesmentioning

confidence: 99%

The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications

et al. 2022

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Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor suppressor proteins. This review summarizes the mechanisms by which EBV modulates different tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor proteins to inactivate them. All these processes result in downregulation and impaired function of tumor suppressors, ultimately promoting malignances.

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Section: Ebv Associated Malignanciesmentioning

confidence: 99%

The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications

et al. 2022

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“…The most common epigenetic alterations in T-Cell lymphoma include the dysregulation of DNA methylation and histone modification through the transfer of acetyl or methyl groups with resultant silencing of tumor suppressor genes and/or expression of proto-oncogenes. DNA methylation within gene regulatory elements is mediated by three members of the DNA methyltransferase (DNMT) family called DNMT1, DNMT3A, and DNMT3B, which execute and maintain methylation of CpG dinucleotides [ 9 ]. DNMT3A, TET2, IDH2, and RHOA mutations predominantly impact DNA methylation and are often observed in AITL as well as other T follicular helper lymphomas [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…DNA methylation within gene regulatory elements is mediated by three members of the DNA methyltransferase (DNMT) family called DNMT1, DNMT3A, and DNMT3B, which execute and maintain methylation of CpG dinucleotides [ 9 ]. DNMT3A, TET2, IDH2, and RHOA mutations predominantly impact DNA methylation and are often observed in AITL as well as other T follicular helper lymphomas [ 9 , 10 ]. Histone modifying enzymes (writers, erasers, chromatin remodelers) edit the histone code and have been implicated in the development of many T-Cell lymphomas, including ATLL, CTCL, PTCL-NOS, AITL, HSTL, and ENKTL [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…DNMT3A, TET2, IDH2, and RHOA mutations predominantly impact DNA methylation and are often observed in AITL as well as other T follicular helper lymphomas [ 9 , 10 ]. Histone modifying enzymes (writers, erasers, chromatin remodelers) edit the histone code and have been implicated in the development of many T-Cell lymphomas, including ATLL, CTCL, PTCL-NOS, AITL, HSTL, and ENKTL [ 9 ]. Genes implicated in histone modification and chromatin remodeling include: KMT2D and KMT2A (encode H3K4 methyltransferases), KDM6A (encodes H3K27 demethylase), SETD2 (encodes H3K36 methyltransferase and recruits DNMT3B), EP300 and CREBBP (encode H3K18 acetyltransferases) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Genetic Landscape of Peripheral T-Cell Lymphoma

Hathuc

Kreisel

2022

Life

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Peripheral T-Cell lymphoma (PTCL) comprises a heterogenous group of uncommon lymphomas derived from mature, post-thymic or “peripheral” T- and natural killer cells. The World Health Organization (WHO) emphasizes a multiparameter approach in the diagnosis and subclassification of these neoplasms, integrating clinical, morphologic, immunophenotypic, and genetic features into the final diagnosis. Clinical presentation is particularly important due to histologic, immunophenotypic and genetic variations within established subtypes, and no convenient immunophenotypic marker of monoclonality exists. In recent years, widespread use of gene expression profiling and next-generation sequencing (NGS) techniques have contributed to an improved understanding of the pathobiology in PTCLs, and these have been incorporated into the 2016 revised WHO classification of mature T- and NK-cell neoplasms which now encompasses nearly 30 distinct entities. This review discusses the genetic landscape of PTCL and its role in subclassification, prognosis, and potential targeted therapy. In addition to discussing T-Cell lymphoma subtypes with relatively well-defined or relevant genetic aberrancies, special attention is given to genetic advances in T-Cell lymphomas of T follicular helper cell (TFH) origin, highlighting genetic overlaps between angioimmunoblastic T-Cell lymphoma (AITL), follicular T-Cell lymphoma, and nodal peripheral T-Cell lymphoma with a TFH phenotype. Furthermore, genetic drivers will be discussed for ALK-negative anaplastic large cell lymphomas and their role in differentiating these from CD30+ peripheral T-Cell lymphoma, not otherwise specified (NOS) and primary cutaneous anaplastic large cell lymphoma. Lastly, a closer look is given to genetic pathways in peripheral T-Cell lymphoma, NOS, which may guide in teasing out more specific entities in a group of T-Cell lymphomas that represents the most common subcategory and is sometimes referred to as a “wastebasket” category.

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“…KMT2D is among the most commonly mutated genes in all types of T-cell lymphomas as well as lymphomas of other lineages and solid tumors,[37][38][39][40] and appears to work in concert with other mutations to facilitate neoplastic transformation. Epigenetic modifying agents have shown promise in the therapy of peripheral T-cell lymphomas 41. It is unclear whether this therapeutic approach will also be beneficial for RCD II patients with KMT2D mutations.The nature and origin of the aberrant IELs in RCD II have recently been questioned.…”

mentioning

confidence: 99%

Refractory celiac disease type II: An atypical case highlighting limitations of the current classification system

Soderquist

Hsiao

Mansukhani

et al. 2020

Hematological Oncology

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Refractory celiac disease (RCD) is a rare condition associated with high morbidity that develops in individuals with celiac disease. It is known to be biologically heterogeneous, and currently two types are recognized based on immunophenotypic and molecular features, type I (RCD I) and type II (RCD II). Differentiating between RCD I and RCD II is critical, as patients with RCD II have substantially worse outcomes and a high risk of developing enteropathy-associated T-cell lymphoma. However, the current RCD classification is limited in scope, and atypical presentations and immunophenotypes are not recognized at present. Herein, we describe a unique case of RCD II with atypical clinical (primarily neurologic manifestations and lack of significant gastrointestinal symptoms), histopathologic (no villous atrophy), immunophenotypic (virtual absence of cytoplasmic CD3 expression), and molecular features (absence of clonal TR rearrangement and identification of pathogenic STAT3 and KMT2D mutations). This case highlights limitations of the current RCD classification system and the utility of next generation sequencing (NGS) studies in the diagnostic workup of RCD. Future algorithms need to recognize extraintestinal manifestations and incorporate atypical histopathologic and immunophenotypic features, as well as results of NGS analysis for RCD II classification.

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Targeting epigenetic regulators in the treatment of T-cell lymphoma

Cited by 8 publications

References 136 publications

The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications

The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications

Genetic Landscape of Peripheral T-Cell Lymphoma

Refractory celiac disease type II: An atypical case highlighting limitations of the current classification system

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