ABSTRACT: The hallmark of follicular lymphoma (FL) is the t(14;18) chromosomal translocation. However, constitutive expression of anti-apoptotic Bcl-2 alone is insufficient for lymphomagenesis and subsequent molecular hits are required. We explored the role of microRNA (miRNA or miR) in the biology of FL by generating miRNA profiles of enriched sorted grade 1 and 2 FL tumor cells derived from 18 patients compared with enriched germinal center B-cells derived from seven follicular hyperplasia (FH). Expression levels of 851 human miRs were assayed and 133 miRs were significantly differentially expressed in FL tumor cells. The expression of 44 miRs in three major groups generated a unique FL signature. MiRs in group 1 were increased in FL (miR-193-5p, -193b*, -345, -513b, -574-3p, -584, -663, -1287, -1295, and -1471). Group 2 was increased in the majority of FL cases but showed lower levels of expression in a subset of FL (let-7a, let-7f, miR-7-1*, -9, -9*, -20a, -20b, -30b, -96, -98, -194, -195, -221*, -374a, -451, -454, -502-3p, -532-3p, -574-3p, -664*, -1274a, -1274b, and -1260). MiR group 3 was decreased in FL (miR-17*, -30a, 33a, 106a*, -141, 202, -205, -222, 301b, -431*, and -570). Two patterns within FL were detected, largely due to the variable expression of group 2 miRs. The pattern with higher expression of group 2 miRs was associated with complete response to chemotherapy. Gene expression analysis of 199 genes related to lymphoma and tumor development performed in tandem indicated differential expression of 47 genes in FL including increased expression of AKT-1, PRKCE, IL4R, DROSHA, and MAPK1; and decreased expression of CHEK1, RAD51, CDKN1A, SOCS2, KLF4, BLIMP1 and IRF4. Functional studies provide evidence that miR-20a and -20b target CDKN1A/p21, miR-194 targets SOCS2, and miR-301b targets MAPK1 in FL, affecting cell proliferation and potentially contributing to lymphomagenesis. These findings suggest a role for aberrant miRNA expression in the biology of FL with prognostic and mechanistic implications.
