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

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.