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

被引：104

作者：

Beguelin, Wendy ^{[1
]}

Teater, Matt ^{[1
,2
]}

Meydan, Cem ^{[2
]}

Hoehn, Kenneth B. ^{[3
]}

Phillip, Jude M. ^{[1
]}

Soshnev, Alexey A. ^{[4
]}

Venturutti, Leandro ^{[1
]}

Rivas, Martin A. ^{[1
]}

Calvo-Fernandez, Maria T. ^{[1
]}

Gutierrez, Johana ^{[1
]}

Camarillo, Jeannie M. ^{[5
]}

Takata, Katsuyoshi ^{[6
]}

Tarte, Karin ^{[7
]}

Kelleher, Neil L. ^{[5
]}

Steidl, Christian ^{[6
]}

Mason, Christopher E. ^{[2
,8
,9
,10
]}

Elemento, Olivier ^{[2
,8
]}

Allis, C. David ^{[4
]}

Kleinstein, Steven H. ^{[3
,11
]}

Melnick, Ari M. ^{[1
]}

机构：

[1] Cornell Univ, Dept Med, Div Hematol Oncol, Weill Cornell Med, New York, NY 10021 USA

[2] Cornell Univ, Weill Cornell Med, Inst Computat Biomed, New York, NY 10021 USA

[3] Yale Sch Med, Dept Pathol, New Haven, CT 06520 USA

[4] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA

[5] Northwestern Univ, Dept Chem Mol Biosci & Natl Resource Translat & D, Evanston, IL 60208 USA

[6] British Columbia Canc, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada

[7] Univ Rennes 1, UMR 1236, INSERM, Etab Francais du Sang, F-35043 Rennes, France

[8] Cornell Univ, Dept Physiol & Biophys, Weill Cornell Med, New York, NY 10021 USA

[9] Weill Cornell Med, WorldQuant Initiat Quantitat Predict, New York, NY 10021 USA

[10] Weill Cornell Med, Feil Family Brain & Mind Res Inst, New York, NY 10021 USA

[11] Yale Univ, Interdept Program Computat Biol & Bioinformat, New Haven, CT 06511 USA

来源：

CANCER CELL | 2020年 / 37卷 / 05期

关键词：

HISTONE METHYLTRANSFERASE EZH2; GERMINAL CENTER FORMATION; B-CELLS; LYSINE; 27; MONOCLONAL-ANTIBODIES; METHYLATION PATTERNS; AFFINITY MATURATION; DYNAMIC REGULATION; GENE-MUTATIONS; C-MYC;

D O I：

10.1016/j.ccell.2020.04.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：655 / +

页数：30

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