title: EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation.
abstract: The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Béguelin
authors.forename: Relja
authors.initials: R
authors.lastname: Popovic
authors.forename: Matt
authors.initials: M
authors.lastname: Teater
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: Karen L
authors.initials: KL
authors.lastname: Bunting
authors.forename: Monica
authors.initials: M
authors.lastname: Rosen
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Teresa
authors.initials: T
authors.lastname: Ezponda
authors.forename: Eva
authors.initials: E
authors.lastname: Martinez-Garcia
authors.forename: Haikuo
authors.initials: H
authors.lastname: Zhang
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Zheng
authors.forename: Sharad K
authors.initials: SK
authors.lastname: Verma
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCabe
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Ott
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Van Aller
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Kruger
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Charles F
authors.initials: CF
authors.lastname: McHugh
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.forename: Neil
authors.initials: N
authors.lastname: Kelleher
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.forename: Caretha L
authors.initials: CL
authors.lastname: Creasy
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009154:Mutation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology
chemical_list: D006657:Histones; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2