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Haematologica. 2016 Nov;101(11):1380-1389. Epub 2016 Jul 6.

Alterations of microRNA and microRNA-regulated messenger RNA expression in germinal center B-cell lymphomas determined by integrative sequencing analysis.

Author information

  • 1Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
  • 2Department of Algorithmic Bioinformatics, Heinrich-Heine University, Duesseldorf, Germany.
  • 3Transcriptome Bioinformatics Group, LIFE Research Center for Civilization Diseases, University of Leipzig, Germany.
  • 4Bioinformatics Group, Department of Computer Science, University of Leipzig, Germany.
  • 5Interdisciplinary Center for Bioinformatics, University of Leipzig, Germany.
  • 6Institute of Pathology, Charité - University Medicine Berlin, Germany.
  • 7Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
  • 8Division Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 9National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • 10German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 11Department of Pediatric Hematology and Oncology, University Hospital Münster, Germany.
  • 12Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
  • 13Department of Human and Animal Cell Cultures, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
  • 14Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 15Department of Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology and Bioquant, Heidelberg University, Germany.
  • 16Friedrich-Ebert Hospital Neumünster, Clinics for Hematology, Oncology and Nephrology, Neumünster, Germany.
  • 17Department of Internal Medicine II: Hematology and Oncology, University Medical Centre, Campus Kiel, Germany.
  • 18Hematopathology Section, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
  • 19EMBL Heidelberg, Genome Biology, Heidelberg, Germany.
  • 20Institute for Medical Informatics Statistics and Epidemiology, Leipzig, Germany.
  • 21Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
  • 22Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
  • 23Hospital of Internal Medicine II, Hematology and Oncology, St-Georg Hospital Leipzig, Germany.
  • 24Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany.
  • 25Institute of Pathology, Medical Faculty of the Ulm University, Germany.
  • 26Department of Pediatric Hematology and Oncology University Hospital Giessen, Germany.
  • 27Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Germany.
  • 28RNomics Group, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.
  • 29Max-Planck-Institute for Mathematics in Sciences, Leipzig, Germany.
  • 30Santa Fe Institute, NM, USA.
  • 31Department of Internal Medicine III, University of Ulm, Germany.
  • 32Department of Hematology and Oncology, Georg-August-University of Göttingen, Germany.


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.

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