Follicular Dendritic Cell (FDC)-Induced Microrna-Mediated up-Regulation of PRDM1 and Down-Regulation of BCL6 in Germinal Center B Lymphocytes: A Potential Mechanism for B-Cell Differentiation.

Abstract 4588

B-cell differentiation process is tightly regulated by suppression or induction of specific transcription factors. Among various transcriptional regulators, BCL6 and PRDM-1 are master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM-1 have been associated with lymphomagenesis. However how these transcription factors are regulated and what determines their expression are unclear. Given that follicular dendritic cells (FDC) closely interact with B cells within the GC, provide survival signal to protect B cells from apoptosis and are essential for the differentiation of GC B cells, we used an in vitro FDC-B-cell co-culture model to explore the role of FDC-B cell interaction and FDC-induced miRNA in the regulation of BCL6 and PRDM-1 expression. In this study 1) we revealed that follicular dendritic cells (FDCs, HK) regulate expression of transcription factor (BCL6, and PRDM1) via cell-cell contact, 2) we showed that FDCs regulate expression of B-cell survival and differentiation-related microRNAs, 3) we demonstrated that microRNAs regulate expression of transcription factors BCl6 and PRDM1 and 4) we documented that follicular dendritic cells regulate expression of transcription factor (BCL6, and PRDM1) through microRNAs and plays an important role in B-differentiation. These studies establish new molecular mechanisms for regulation of BCL6 and PRDM-1. FDC-induce miRNA mediated down- and up-regulation of transcriptional factors may contribute to the phenotype maintenance of GC, and pathogenesis of non-Hodgkin's lymphoma (NHL) by interfering with normal B-cell terminal differentiation.