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• Vrzalikova, K
• Leonard, S
• Fan, Y
• Bell, A
• Vockerodt, M
• Flodr, P
• Wright, K
• Rowe, M
• Tao, Q
• Murray, P
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• Vrzalikova, K
• Leonard, S
• Fan, Y
• Bell, A
• Vockerodt, M
• Flodr, P
• Wright, K
• Rowe, M
• Tao, Q
• Murray, P
• [+] on PubMed
• Vrzalikova, K
• Leonard, S
• Fan, Y
• Bell, A
• Vockerodt, M
• Flodr, P
• Wright, K
• Rowe, M
• Tao, Q
• Murray, P

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Pathogens 2012, 1(2), 83-101; doi:10.3390/pathogens1020083

Article

Hypomethylation and Over-Expression of the Beta Isoform of BLIMP1 is Induced by Epstein-Barr Virus Infection of B Cells; Potential Implications for the Pathogenesis of EBV-Associated Lymphomas

Katerina Vrzalikova ^1,2,†,* , Sarah Leonard ^1,† , Yichao Fan ³ , Andrew Bell ¹ , Martina Vockerodt ¹ , Patrik Flodr ² , Kenneth L. Wright ⁴ , Martin Rowe ¹ , Qian Tao ³  and Paul G. Murray ^1,2

¹ School of Cancer Sciences, University of Birmingham, B15 2TT, UK ² Laboratory of Molecular Pathology, Department of Pathology, and Institute of Molecular and Translation Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, 779 00, Czech Republic ³ The Cancer Epigenetics Laboratory, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, 999077, Hong Kong ⁴ H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, MRC-4 East, Tampa, FL 33612, USA ^† These authors contributed equally to this work.

* Author to whom correspondence should be addressed.

Received: 15 August 2012; in revised form: 19 September 2012 / Accepted: 24 September 2012 / Published: 8 October 2012

(This article belongs to the Special Issue Infection and Cancer)

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Abstract: B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin’s lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas.

Keywords: BLIMP1; Epstein-Barr virus; hypomethylation; Hodgkin’s lymphoma

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