Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL.

Stefan Nagel,Wilhelm G Dirks,Corinna Meyer,Claudia Pommerenke,Hans G Drexler,Cord C Uphoff,Joseph S Pagano

doi:10.1371/journal.pone.0216898

Stefan Nagel, Wilhelm G Dirks + Show 5 more

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https://doi.org/10.1371/journal.pone.0216898

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Abstract

NKL homeobox genes encode developmental transcription factors regulating basic processes in cell differentiation. According to their physiological expression pattern in early hematopoiesis and lymphopoiesis, particular members of this homeobox gene subclass constitute an NKL-code. B-cell specific NKL-code genes generate a regulatory network and their deregulation is implicated in B-cell lymphomagenesis. Epstein-Barr virus (EBV) infects B-cells and influences the activity of signalling pathways including JAK/STAT and several genes encoding developmental regulators. Therefore, EBV-infection impacts the pathogenesis and the outcome of B-cell malignancies including Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL). Here, we isolated EBV-positive and EBV-negative subclones from the DLBCL derived cell line DOHH-2. These subclones served as models to investigate the role of EBV in deregulation of the B-cell specific NKL-code members HHEX, HLX, MSX1 and NKX6-3. We showed that the EBV-encoded factors LMP1 and LMP2A activated the expression of HLX via STAT3. HLX in turn repressed NKX6-3, SPIB and IL4R which normally mediate plasma cell differentiation. In addition, HLX repressed the pro-apoptotic factor BCL2L11/BIM and hence supported cell survival. Thus, EBV aberrantly activated HLX in DLBCL, thereby disturbing both B-cell differentiation and apoptosis. The results of our study appreciate the pathogenic role of EBV in NKL homeobox gene deregulation and B-cell malignancies.

Highlights

Hematopoietic stem cells reside in the bone marrow and generate precursor cells for the myeloid and lymphoid lineages
To determine the latency program operating in Epstein-Barr virus (EBV)-positive DOHH-2 subclones we performed Reverse transcription (RT)-polymerase chain-reaction (PCR) analysis of selected EBV-encoded genes (Fig 1C)
We showed that EBV-encoded LMP1 and LMP2A activated the expression of NKL homeobox gene HLX

Summary

Introduction

Hematopoietic stem cells reside in the bone marrow and generate precursor cells for the myeloid and lymphoid lineages. The last steps of B-cell development take place in the germinal centers which are located in lymphoid organs. They include the differentiation into plasma cells (CD38+ CD138+ surface IgG-) or memory B-cells (CD38- CD138- surface IgG+) which express particular cell type specific factors. Several transcription factors like BCL6 and PAX5 act as master genes/factors for B-cell development [1,2]. Their deregulation or mutation contributes to cell transformation and lymphomagenesis [3].

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