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Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation
Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic ly...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557053/ https://www.ncbi.nlm.nih.gov/pubmed/25820993 http://dx.doi.org/10.1002/path.4539 |
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author | Merkel, Olaf Hamacher, Frank Griessl, Robert Grabner, Lisa Schiefer, Ana-Iris Prutsch, Nicole Baer, Constance Egger, Gerda Schlederer, Michaela Krenn, Peter William Hartmann, Tanja Nicole Simonitsch-Klupp, Ingrid Plass, Christoph Staber, Philipp Bernhard Moriggl, Richard Turner, Suzanne D Greil, Richard Kenner, Lukas |
author_facet | Merkel, Olaf Hamacher, Frank Griessl, Robert Grabner, Lisa Schiefer, Ana-Iris Prutsch, Nicole Baer, Constance Egger, Gerda Schlederer, Michaela Krenn, Peter William Hartmann, Tanja Nicole Simonitsch-Klupp, Ingrid Plass, Christoph Staber, Philipp Bernhard Moriggl, Richard Turner, Suzanne D Greil, Richard Kenner, Lukas |
author_sort | Merkel, Olaf |
collection | PubMed |
description | Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(−)), which is characterized by a worse prognosis. We found that ALCL ALK(−), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(−), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(−) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
format | Online Article Text |
id | pubmed-4557053 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-45570532015-09-08 Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation Merkel, Olaf Hamacher, Frank Griessl, Robert Grabner, Lisa Schiefer, Ana-Iris Prutsch, Nicole Baer, Constance Egger, Gerda Schlederer, Michaela Krenn, Peter William Hartmann, Tanja Nicole Simonitsch-Klupp, Ingrid Plass, Christoph Staber, Philipp Bernhard Moriggl, Richard Turner, Suzanne D Greil, Richard Kenner, Lukas J Pathol Original Papers Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(−)), which is characterized by a worse prognosis. We found that ALCL ALK(−), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(−), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(−) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. John Wiley & Sons, Ltd 2015-08 2015-04-27 /pmc/articles/PMC4557053/ /pubmed/25820993 http://dx.doi.org/10.1002/path.4539 Text en © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Papers Merkel, Olaf Hamacher, Frank Griessl, Robert Grabner, Lisa Schiefer, Ana-Iris Prutsch, Nicole Baer, Constance Egger, Gerda Schlederer, Michaela Krenn, Peter William Hartmann, Tanja Nicole Simonitsch-Klupp, Ingrid Plass, Christoph Staber, Philipp Bernhard Moriggl, Richard Turner, Suzanne D Greil, Richard Kenner, Lukas Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation |
title | Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation |
title_full | Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation |
title_fullStr | Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation |
title_full_unstemmed | Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation |
title_short | Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation |
title_sort | oncogenic role of mir-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation |
topic | Original Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557053/ https://www.ncbi.nlm.nih.gov/pubmed/25820993 http://dx.doi.org/10.1002/path.4539 |
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