Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response.

Animals B-Lymphocytes / immunology Cell Transformation, Neoplastic / genetics Cellular Reprogramming Dendritic Cells / immunology Enhancer of Zeste Homolog 2 Protein / genetics Female Germinal Center / immunology Humans Lymphoma, B-Cell / genetics Lymphoma, Follicular / genetics Mice Mice, Inbred C57BL Mutation
EZH2 epigenetic dysregulation follicular lymphoma germinal center immune microenvironment

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
11 05 2020
Historique:
received: 07 10 2019
revised: 04 02 2020
accepted: 08 04 2020
entrez: 13 5 2020
pubmed: 13 5 2020
medline: 4 11 2020
Statut: ppublish

Résumé

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.

Identifiants

DOI: 10.1016/j.ccell.2020.04.004 PMID: 32396861 PMC: PMC7298875
pubmed: 32396861
pii: S1535-6108(20)30203-8
doi: 10.1016/j.ccell.2020.04.004
pmc: PMC7298875
mid: NIHMS1585838
pii:
doi:

Substances chimiques

EZH2 protein, human EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein EC 2.1.1.43

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

655-673.e11

Subventions

Organisme : NCI NIH HHS
ID : R01 CA198089
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220499
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM108569
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI104739
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests A.M.M. is consulting for Epizyme and Constellation Pharmaceuticals, and receives research funding from Janssen Pharmaceuticals; S.H.K. is consulting for Northrop Grumman; C.E.M. is a co-founder and equity stake holder for Onegevity Health and Biotia, Inc.; C.S. has performed consultancy for Seattle Genetics, Curis Inc., Roche, AbbVie, Juno Therapeutics, and Bayer, and has received research funding from Bristol-Myers Squibb and Trillium Therapeutics, Inc. There are no competing interests.

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Auteurs

Wendy Béguelin (W)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address: web2002@med.cornell.edu.

Matt Teater (M)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

Cem Meydan (C)

Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

Kenneth B Hoehn (KB)

Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.

Jude M Phillip (JM)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

Alexey A Soshnev (AA)

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.

Leandro Venturutti (L)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

Martín A Rivas (MA)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

María T Calvo-Fernández (MT)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

Johana Gutierrez (J)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

Jeannie M Camarillo (JM)

Department of Chemistry, Molecular Biosciences and the National Resource for Translational and Developmental Proteomics, Northwestern University, Evanston, IL 60208, USA.

Katsuyoshi Takata (K)

Center for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.

Karin Tarte (K)

UMR 1236, Université Rennes 1, INSERM, Etablissement Français du Sang, 35043 Rennes, France.

Neil L Kelleher (NL)

Department of Chemistry, Molecular Biosciences and the National Resource for Translational and Developmental Proteomics, Northwestern University, Evanston, IL 60208, USA.

Christian Steidl (C)

Center for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC V5Z 1L3, Canada.

Christopher E Mason (CE)

Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; The WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY 10021, USA; The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA.

Olivier Elemento (O)

Institute for Computational Biomedicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA.

C David Allis (CD)

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.

Steven H Kleinstein (SH)

Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA; Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06511, USA.

Ari M Melnick (AM)

Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA. Electronic address: amm2014@med.cornell.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes B › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › Transformation cellulaire néoplasique › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Phénomènes génétiques › Reprogrammation cellulaire › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Système phagocytaire mononucléé › Cellules dendritiques › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Protéines du groupe Polycomb › Complexe répresseur Polycomb-2 › Protéine-2 homologue de l'activateur de Zeste › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Système lymphatique › Tissu lymphoïde › Noeuds lymphatiques › Centre germinatif › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome B › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome folliculaire › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Mutant EZH2 Induces a Pre-malignant Lymphoma...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutant EZH2 Induces a Pre-malignant Lymphoma...