Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggresive B-cell lymphoma

We studied the global miRNA expression in diffuse large B-cell lymphoma (DLBCL; n=79), Burkitt lymphoma (BL; n= 36), primary mediastinal B-cell lymphoma (PMBL; n=12), B-cell lines (n=11), and normal subsets of naïve B-cells (N), centroblasts (CB), and peripheral blood B-cells along with their corresponding gene expression profiles (GEP). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared to ABC-DLBCL (p=0.002). We identified a 27-miRNA signature that included MYC targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155 which significantly associated with R-CHOP response failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to AKT inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.