Characterization of human CS1 gene promoter in NK and B cells (IRM7P.485)

Abstract

Abstract CS1 (CRACC, SLAMF7 or CD319) is a member of SLAM (Signaling Lymphocyte Activation Molecule) family receptors and is expressed on NK cells, CD8+ T lymphocytes, mature dendritic cells and activated B cells. Unlike other SLAM members, CS1 shows SAP (SLAM-associated protein) independent but EAT-2 (Ewing’s Sarcoma associated transcript) dependent signaling in human NK cells. CS1 has been shown to be overexpressed in multiple myeloma (MM) and a humanized monoclonal antibody against CS1 is in phase 2 clinical trial for MM. In this study, we analyzed the transcriptional regulation of human CS1 gene. In contrast to the multiple transcription initiation sites in human and mouse 2B4 genes that are driven by TATA-less promoters, we found that proximal region of CS1 promoter contains CAAT box and atypical TATA-box that might result in common transcription initiation at -29 nucleotides upstream of the ATG translation start codon. Relative luciferase activities of successive deletion mutants of CS1 promoter were different between Blimp-1-positive YT cells and Blimp-1-negative DB cells. Our electrophoretic mobility shift assay indicates that Blimp-1 binds to putative Blimp-1 binding site at -750 to -746 region of CS1 promoter. This suggests a possible activating role of Blimp-1 transcription factor in certain circumstances. Understanding CS1 gene expression and regulation will help in developing immune based therapy for B cell-mediated diseases, such as SLE and MM.