An Expanded Set of Direct BLIMP-1 Targets Identifies Novel Links in Differentiation, Immune Response and Lymphoma.

Abstract 1466

Poster Board I-489

B-lymphocyte induced maturation protein 1 (BLIMP-1) has been defined as a key driver of the genetic reprogramming during differentiation of B-cells to plasma cells. Frequent inactivation of PRDM1, the BLIMP-1 gene, in diffuse large B-cell lymphoma (DLBCL) indicates that loss of function is an important event in lymphomagenesis. Only a limited set of direct BLIMP-1 target genes have been defined. In order to better understand the function of human BLIMP-1 in differentiation and malignancy we have established a more comprehensive set of occupied promoters. These data provide an extended view of the regulatory network controlled by BLIMP-1, and identify novel sets of targets involved in transcription and immune response. The composition of occupied promoters identifies complexity in BLIMP-1 binding motif selection, and substantial overlap between BLIMP-1 sites and Interferon regulatory factor (IRF) elements. Consistent with active competition between BLIMP-1 and IRFs, target genes associated with such overlapping motifs are found to be preferentially induced in response to BLIMP-1 knockdown. Finally BLIMP-1 targets are found to include key components of DLBCL gene expression signatures. This map of BLIMP-1 occupied promoters thus illuminates key aspects of function in normal and malignant cell biology.