EBNA2 and c-myc in B Cell Immortalization by Epstein-Barr Virus and in the Pathogenesis of Burkitt’s Lymphoma

Zimber-Strobl, Ursula; Strobl, Lothar J.; Höfelmayr, Heike; Kempkes, Bettina; Staege, Martin S.; Laux, Gerhard; Christoph, Barbara; Polack, Axel; Bornkamm, Georg W.

doi:10.1007/978-3-642-60162-0_39

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…In culture, EBV positive BL cells tend to drift to a latency III state, with the induction of the other viral latent genes. This is likely to have a significant impact on the tumorigenic environment, exemplified by the action of EBNA2 upon c-Myc 39 and the cells lose sensitivity to Mdm2 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Lymphomas driven by Epstein–Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2

et al. 2018

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Epstein-Barr virus (EBV) associated Burkitt’s lymphoma is characterised by the deregulation of c-Myc expression and a restricted viral gene expression pattern in which the EBV nuclear antigen-1 (EBNA1) is the only viral protein to be consistently expressed. EBNA1 is required for viral genome propagation and segregation during latency. However, it has been much debated whether the protein plays a role in viral-associated tumourigenesis. We show that the lymphomas which arise in EµEBNA1 transgenic mice are unequivocally linked to EBNA1 expression and that both C-Myc and Mdm2 deregulation are central to this process. Tumour cell survival is supported by IL-2 and there is a skew towards CD8 positive T-cells in the tumour environment, while the immune check-point protein PD-L1 is upregulated in the tumours. Additionally, several isoforms of Mdm2 are upregulated in the EµEBNA1 tumours, with increased phosphorylation at ser166, an expression pattern not seen in Eµc-Myc transgenic tumours. Concomitantly, E2F1, Xiap, Mta1, C-Fos and Stat1 are upregulated in the tumours. Using four independent inhibitors of Mdm2 we demonstrate that the EµEBNA1 tumour cells are dependant upon Mdm2 for survival (as they are upon c-Myc) and that Mdm2 inhibition is not accompanied by upregulation of p53, instead cell death is linked to loss of E2F1 expression, providing new insight into the underlying tumourigenic mechanism. This opens a new path to combat EBV-associated disease.

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Section: Discussionmentioning

confidence: 99%

Lymphomas driven by Epstein–Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2

et al. 2018

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“…Because EBNA3A, -B, and -C are EBNA2 targets, they are likely not to be expressed, but final evidence for this absence of expression is missing because of lack of reagents for EBV type II EBNA3 proteins. We have shown that c-myc-transfected EREB cells (including A1) grow in single cell suspension and have down-regulated activation markers, adhesion molecules, and the costimulatory molecules CD80 and CD86 (21,23,32). HLA class I expression is reduced in A1 as compared with EREB2-5 cells by a factor of three as revealed by staining with the framework antibody W6͞32 (Table 1).…”

Section: A1 Cells Have Lost Their Ability To Stimulate Allogeneic T Cmentioning

confidence: 93%

MYC overexpression imposes a nonimmunogenic phenotype on Epstein–Barr virus-infected B cells

Staege

Lee

Frisan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Several events can cooperate with Myc during lymphomagenesis, such as infection by the Epstein ± Barr virus (Zimber-Strobl et al, 1999;Kulwichit et al, 1998;Wilson et al, 1996) and activation of bcl-1 (Lovec et al, 1994) or bcl-2 (Pegoraro et al, 1984;Strasser et al, 1990;Fanidi et al, 1992). However, the one protein most consistently implicated in Mycinduced lymphomagenesis is p53.…”

mentioning

confidence: 99%

A non-transgenic mouse model for B-cell lymphoma: in vivo infection of p53-null bone marrow progenitors by a Myc retrovirus is sufficient for tumorigenesis

Thomas-Tikhonenko

2002

Oncogene

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The c-Myc oncoprotein is strongly implicated in B-cell neoplasms such as human Burkitt lymphomas and mouse plasmocytomas. Transgenic mice in which the myc gene is juxtaposed to an immunoglobulin enhancer (Em-myc) also develop B-cell lymphomas, but relatively late in life. In addition, these neoplasms are invariably clonal, suggesting the involvement of additional mutations. Such mutations frequently aect the p53 tumour suppressor gene or its positive regulator Arf, hinting that inactivation of the p53 pathway might be the second hit required for the progression towards malignancy. However, even tumours arising in Em-myc/Arf-null animals are thought to be clonal. This observation raised doubts whether overexpression of Myc in p53-null B-cell precursors is sucient for tumorigenesis. To address this question, we have established a new, non-transgenic mouse model of B-lymphoma. This model is based on isolation of primary bone marrow (BM) cells, admixing them with packaging cells producing a Myc-encoding retrovirus (LMycSN), and subcutaneous injection into a host with which BM cells are syngeneic. Predictably, wild type BM cells infected in vivo by LMycSN were not tumorigenic. However, LMycSN-infected p53-null BM cells readily gave rise to B-cell lymphomas composed predominantly of late pro-B/small pre-B-cells. In these tumours, heavy chain gene rearrangements were analysed using two independent PCR-based assays. All neoplasms with DJrearrangements were found to be polyclonal. This result suggests that inactivation of p53 and overexpression of Myc is all that is necessary for the development of fulledged B-lymphomas. Our model would also be instrumental in assessing the transforming potential of Myc mutants and in studying cooperation between Myc and other oncogenes.

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EBNA2 and c-myc in B Cell Immortalization by Epstein-Barr Virus and in the Pathogenesis of Burkitt’s Lymphoma

Cited by 9 publications

References 20 publications

Lymphomas driven by Epstein–Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2

Lymphomas driven by Epstein–Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2

MYC overexpression imposes a nonimmunogenic phenotype on Epstein–Barr virus-infected B cells

A non-transgenic mouse model for B-cell lymphoma: in vivo infection of p53-null bone marrow progenitors by a Myc retrovirus is sufficient for tumorigenesis

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