Haematologica (Nov 2016)
Alterations of microRNA and microRNA-regulated messenger RNA expression in germinal center B-cell lymphomas determined by integrative sequencing analysis
- Kebria Hezaveh,
- Andreas Kloetgen,
- Stephan H Bernhart,
- Kunal Das Mahapatra,
- Dido Lenze,
- Julia Richter,
- Andrea Haake,
- Anke K Bergmann,
- Benedikt Brors,
- Birgit Burkhardt,
- Alexander Claviez,
- Hans G Drexler,
- Roland Eils,
- Siegfried Haas,
- Steve Hoffmann,
- Dennis Karsch,
- Wolfram Klapper,
- Kortine Kleinheinz,
- Jan Korbel,
- Helene Kretzmer,
- Markus Kreuz,
- Ralf Küppers,
- Chris Lawerenz,
- Ellen Leich,
- Markus Loeffler,
- Luisa Mantovani-Loeffler,
- Cristina López,
- Alice C McHardy,
- Peter Möller,
- Marius Rohde,
- Philip Rosenstiel,
- Andreas Rosenwald,
- Markus Schilhabel,
- Matthias Schlesner,
- Ingrid Scholz,
- Peter F Stadler,
- Stephan Stilgenbauer,
- Stéphanie Sungalee,
- Monika Szczepanowski,
- Lorenz Trümper,
- Marc A Weniger,
- Reiner Siebert,
- Arndt Borkhardt,
- Michael Hummel,
- Jessica I. Hoell
Affiliations
- Kebria Hezaveh
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
- Andreas Kloetgen
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany;Department of Algorithmic Bioinformatics, Heinrich-Heine University, Duesseldorf, Germany
- Stephan H Bernhart
- Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany;Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany;Interdisciplinary Center for Bioinformatics, University of Leipzig, Germany
- Kunal Das Mahapatra
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
- Dido Lenze
- Institute of Pathology, Charité – University Medicine Berlin, Germany
- Julia Richter
- Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Andrea Haake
- Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Anke K Bergmann
- Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Benedikt Brors
- Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany;National Center for Tumor Diseases (NCT), Heidelberg, Germany;German Cancer Consortium (DKTK), Heidelberg, Germany
- Birgit Burkhardt
- Department of Pediatric Hematology and Oncology, University Hospital Münster, Germany
- Alexander Claviez
- Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Germany
- Hans G Drexler
- Department of Human and Animal Cell Cultures, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
- Roland Eils
- Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and Bioquant, Heidelberg University, Germany
- Siegfried Haas
- Friedrich-Ebert Hospital Neumünster, Clinics for Hematology, Oncology and Nephrology, Neumünster, Germany
- Steve Hoffmann
- Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany;Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany
- Dennis Karsch
- Department of Internal Medicine II: Hematology and Oncology, University Medical Centre, Campus Kiel, Germany
- Wolfram Klapper
- Hematopathology Section, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Kortine Kleinheinz
- Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Jan Korbel
- EMBL Heidelberg, Genome Biology, Heidelberg, Germany
- Helene Kretzmer
- Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany;Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany
- Markus Kreuz
- Institute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany
- Ralf Küppers
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany
- Chris Lawerenz
- Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Ellen Leich
- Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
- Markus Loeffler
- Institute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany
- Luisa Mantovani-Loeffler
- Hospital of Internal Medicine II, Hematology and Oncology, St-Georg Hospital Leipzig, Germany
- Cristina López
- Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Alice C McHardy
- Department of Algorithmic Bioinformatics, Heinrich-Heine University, Duesseldorf, Germany;Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany
- Peter Möller
- Institute of Pathology, Medical Faculty of the Ulm University, Germany
- Marius Rohde
- Department of Pediatric Hematology and Oncology University Hospital Giessen, Germany
- Philip Rosenstiel
- Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Andreas Rosenwald
- Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany
- Markus Schilhabel
- Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Matthias Schlesner
- Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Ingrid Scholz
- Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany
- Peter F Stadler
- Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany;Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany;Interdisciplinary Center for Bioinformatics, University of Leipzig, Germany;RNomics Group, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany;Max-Planck-Institute for Mathematics in Sciences, Leipzig, Germany;Santa Fe Institute, NM, USA
- Stephan Stilgenbauer
- Department of Internal Medicine III, University of Ulm, Germany
- Stéphanie Sungalee
- EMBL Heidelberg, Genome Biology, Heidelberg, Germany
- Monika Szczepanowski
- Hematopathology Section, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Lorenz Trümper
- Department of Hematology and Oncology, Georg-August-University of Göttingen, Germany
- Marc A Weniger
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany
- Reiner Siebert
- Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany
- Arndt Borkhardt
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
- Michael Hummel
- Institute of Pathology, Charité – University Medicine Berlin, Germany
- Jessica I. Hoell
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany
- DOI
- https://doi.org/10.3324/haematol.2016.143891
- Journal volume & issue
-
Vol. 101,
no. 11
Abstract
MicroRNA are well-established players in post-transcriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNA/target messenger RNA interaction is mostly lacking. Within the International Cancer Genome Consortium Project “Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing”, we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas. Twenty-two miRNA separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC. Moreover, we found expression of three hitherto unreported microRNA. Additionally, we detected recurrent mutations of hsa-miR-142 in diffuse large B-cell lymphomas and follicular lymphomas, and editing of the hsa-miR-376 cluster, providing evidence for microRNA editing in lymphomagenesis. To interrogate the direct physical interactions of microRNA with messenger RNA, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments. MicroRNA directly targeted 208 messsenger RNA in the Burkitt lymphomas and 328 messenger RNA in the non-Burkitt lymphoma models. This integrative analysis discovered several regulatory pathways of relevance in lymphomagenesis including Ras, PI3K-Akt and MAPK signaling pathways, also recurrently deregulated in lymphomas by mutations. Our dataset reveals that messenger RNA deregulation through microRNA is a highly relevant mechanism in lymphomagenesis.