Alterations of miRNAs and miRNA-regulated mRNA expression in GC B cell lymphomas determined by integrative sequencing analysis.

Authors:
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, Séphanie Sungalee, Monika Szczepanowski, Lorenz Trümper, Marc A Weniger, Reiner Siebert, Arndt Borkhardt, Michael Hummel, Jessica I Hoell
Year of publication:
2016
Volume:
-
Issue:
-
Issn:
0390-6078
Journal title abbreviated:
HAEMATOL-HEMATOL J
Journal title long:
Haematologica
Impact factor:
7.702
Abstract:
MicroRNAs are well-established players in posttranscriptional gene regulation. However, information on the effects of microRNA deregulation mainly relies on bioinformatic prediction of potential targets, whereas proof of the direct physical microRNAs/target mRNAs interaction is mostly lacking. Within the International Cancer Genome Consortium Project Determining Molecular Mechanisms in Malignant Lymphoma by Sequencing (ICGC MMML-Seq), we performed miRnome sequencing from 16 Burkitt lymphomas, 19 diffuse large B-cell lymphomas, and 21 follicular lymphomas. Twenty-two miRNAs separated Burkitt lymphomas from diffuse large B-cell lymphomas/follicular lymphomas, of which 13 have shown regulation by MYC. Moreover, we show expression of three hitherto unreported microRNAs. Additionally, we detect 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 microRNAs with mRNAs, we performed Argonaute-2 photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation experiments. MicroRNAs directly targeted 208 mRNAs in the Burkitt lymphomas and 328 mRNAs 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 uncovers in detail the mRNA deregulation through microRNAs as a highly relevant mechanism in lymphomagenesis.