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

Abstract

We studied the global microRNA (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, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). 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 with activated B-cell (ABC)-DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (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 is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL.

• Authors: Javeed Iqbal, Yulei Shen, Xin Huang, Yanyan Liu, Laura Wake, Cuiling Liu, Karen Deffenbacher, Cynthia M Lachel, Chao Wang, Joseph Rohr, Shuangping Guo, Lynette M Smith, George Wright, Sharathkumar Bhagavathi, Karen Dybkaer, Kai Fu, Timothy C Greiner, Julie M Vose, Elaine Jaffe, Lisa Rimsza, Andreas Rosenwald, German Ott, Jan Delabie, Elias Campo, Rita M Braziel, James R Cook, Raymond R Tubbs, James O Armitage, Dennis D Weisenburger, Louis M Staudt, Randy D Gascoyne, Timothy W McKeithan, Wing C Chan
• Journal: Blood (Blood) Vol. 125 Issue 7 Pg. 1137-45 (Feb 12 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25498913 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• MicroRNAs

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics, metabolism)
• Cell Line, Tumor
• Child
• Child, Preschool
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Lymphoma, B-Cell (classification, genetics, pathology)
• Male
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Neoplasm Invasiveness
• Oligonucleotide Array Sequence Analysis
• Prognosis
• Transcriptome
• Young Adult