Purpose Of Review: Perturbation of the epigenome is emerging as a central driving force in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma. The purpose of this review is to explain how alteration of different layers of the epigenome contributes to the biology and clinical features of these tumors.
Recent Findings: Key new findings implicate DNA methylation heterogeneity as a core feature of DLBCL. Epigenetic diversity is linked to unfavorable clinical outcomes, clonal selection at relapse, and is driven at least in part because of the actions of activation-induced cytosine deaminase, which is a unique feature of B-cell lymphomas. Somatic mutations in histone modifier genes drive lymphomagenesis through the establishment of aberrant gene-specific histone modification signatures. For example, EZH2 somatic mutations drive silencing of bivalent gene promoters through histone 3 lysine 27 trimethylation, whereas KMT2D (MLL2) mutations disrupt specific sets of enhancers through depletion of histone 3 lysine 4 mono and dimethylation (H3K4me1/me2).
Summary: Appreciation of the epigenome in determining lymphoma clonal heterogeneity and in driving lymphoma phenotypes through altered promoter and enhancer histone modification profiles is leading to a paradigm shift in how we understand and design therapies for DLBCL and follicular lymphoma.
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