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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

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

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.

PMID:
27390358
PMCID:
PMC5394868
DOI:
10.3324/haematol.2016.143891
[Indexed for MEDLINE]
Free PMC Article

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