Integrative Analysis of MicroRNA and Gene Expression Profiling Contributes to Understand Mantle Cell Lymphoma Pathogenesis.

Abstract 2936

Poster Board II-912

Mantle cell lymphoma (MCL) pathogenesis is still partially unexplained. Although the overexpression of CyclinD1 dependent of t(11;14) is a distinctive molecular hallmark of this neoplasm, this event alone cannot account for the increased survival signaling that characterizes this lymphoma type. Here we investigate whether microRNA (miRNA) expression profile may help to explain the changes in the expression of gene pathways that are characteristic of MCL.

Twenty-three frozen MCL samples, 11 frozen control tissues (7 lymph nodes and 4 tonsils), 8 MCL cell lines and 3 samples of CD19⁺IgD⁺CD27^- cells obtained from tonsils, were studied for miRNAs and gene expression. MiRNA one color microarray data for 470 human miRNA were analyzed using SAM (Significance Analysis of Microarrays) algorithm. MiRNA targets were predicted by miRanda and TargetScan methods. Pathways identification and analysis was carried out by GSEA (Gene Set Enrichment Analysis) online resource.

The analysis of 23 MCL cases compared to 11 control tissues showed a miRNA signature that included 117 miRNAs with FDR<0.05, 85 of which downregulated and 32 upregulated. Combined analysis of these miRNAs and changes in the gene expression profile, paired with bioinformatic target prediction, revealed a group of genes and pathways potentially targeted by the miRNAs, including essential pathways for lymphoma survival. An interesting correspondence was found between the simultaneous increase in CD40, MAPK, NFKB and others pathway signaling with the downregulation of 15 miRNA predicted to target genes belonging to these pathways. Functional validation in MCL cell lines demonstrated NF-kB nuclear translocation to be regulated by the expression of one of these miRNAs. Most of the MCL cell lines exhibit a strong expression of the mir-17-92 polycistron (Oncomir-1).

MiRNAs were used also for the identification of survival prognostic markers; using different analysis (22 frozen specimens) and validation (54 paraffin embedded cases) series. A single miRNA distinguished a group of MCL cases with a 72.2% survival at 60 m.

This study identifies a set of miRNAS involved in MCL pathogenesis, which could be used in MCL recognition and clinical prognostication.