Functional interplay of Epstein -Barr virus oncoproteins in a mouse model of B cell

被引：18

作者：

Sommermann, Thomas ^{[1
]}

Yasuda, Tomoharu ^{[1
]}

Ronen, Jonathan ^{[2
]}

Wirtz, Tristan ^{[1
]}

Weber, Timm ^{[1
]}

Sack, Ulrike ^{[1
]}

Caeser, Rebecca ^{[3
]}

Zhang, Jingwei ^{[1
]}

Li, Xun ^{[1
]}

Van Trung Chu ^{[1
]}

Jauch, Anna ^{[4
]}

Unger, Kristian ^{[5
,6
]}

Hodson, Daniel J. ^{[3
]}

Akalin, Altuna ^{[2
]}

Rajewsky, Klaus ^{[1
]}

机构：

[1] Max Delbruck Ctr Mol Med, Dept Canc Res, D-13215 Berlin, Germany

[2] Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, D-10115 Berlin, Germany

[3] Univ Cambridge, Wellcome Med Res Council Cambridge Stem Cell Inst, Dept Haematol, Cambridge CB2 0AF, England

[4] Heidelberg Univ, Inst Human Genet, D-69120 Heidelberg, Germany

[5] Helmholtz Zentrum Munchen, Res Unit Radiat Cytogenet, D-85764 Neuherberg, Germany

[6] Ludwig Maximilian Univ Munich, Univ Hosp, Dept Radiat Oncol, D-81377 Munich, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2020年 / 117卷 / 25期

基金：

英国医学研究理事会; 欧洲研究理事会;

关键词：

Epstein-Barr virus; LMP1; EBNA; B cell lymphomagenesis; plasma cell differentiation; NF-KAPPA-B; TUMOR-SUPPRESSOR; LYMPHOPROLIFERATIVE DISORDERS; IMMUNE SURVEILLANCE; NUCLEAR ANTIGEN-1; GENOME-WIDE; IN-VIVO; C-REL; EBV; EXPRESSION;

D O I：

10.1073/pnas.1921139117

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.

引用

页码：14421 / 14432

页数：12

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