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

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 NK...

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Autores principales: Nagel, Stefan, Uphoff, Cord C., Dirks, Wilhelm G., Pommerenke, Claudia, Meyer, Corinna, Drexler, Hans G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541347/
https://www.ncbi.nlm.nih.gov/pubmed/31141539
http://dx.doi.org/10.1371/journal.pone.0216898
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author Nagel, Stefan
Uphoff, Cord C.
Dirks, Wilhelm G.
Pommerenke, Claudia
Meyer, Corinna
Drexler, Hans G.
author_facet Nagel, Stefan
Uphoff, Cord C.
Dirks, Wilhelm G.
Pommerenke, Claudia
Meyer, Corinna
Drexler, Hans G.
author_sort Nagel, Stefan
collection PubMed
description 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.
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spelling pubmed-65413472019-06-05 Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL Nagel, Stefan Uphoff, Cord C. Dirks, Wilhelm G. Pommerenke, Claudia Meyer, Corinna Drexler, Hans G. PLoS One Research Article 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. Public Library of Science 2019-05-29 /pmc/articles/PMC6541347/ /pubmed/31141539 http://dx.doi.org/10.1371/journal.pone.0216898 Text en © 2019 Nagel et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nagel, Stefan
Uphoff, Cord C.
Dirks, Wilhelm G.
Pommerenke, Claudia
Meyer, Corinna
Drexler, Hans G.
Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL
title Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL
title_full Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL
title_fullStr Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL
title_full_unstemmed Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL
title_short Epstein-Barr virus (EBV) activates NKL homeobox gene HLX in DLBCL
title_sort epstein-barr virus (ebv) activates nkl homeobox gene hlx in dlbcl
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541347/
https://www.ncbi.nlm.nih.gov/pubmed/31141539
http://dx.doi.org/10.1371/journal.pone.0216898
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