title: The many layers of epigenetic dysfunction in B-cell lymphomas.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: aWeill Cornell Cancer Center bDepartment of Physiology and Biophysics cDepartment of Medicine, Weill Cornell Medicine, New York City, New York, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: Pilar M
authors.initials: PM
authors.lastname: Dominguez
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D060965:Clonal Evolution / Q000235:genetics; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000628:therapy; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D003596:Cytosine; D049308:Dioxygenases; C541081:TET2 protein, human; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase