CEACAM1 Orchestrates Lipid Raft Dynamics and B-cell Receptor Signaling in Mantle Cell Lymphoma

B-cell receptor (BCR) signaling plays an important role in the pathogenesis of mantle cell lymphoma (MCL), but the detailed mechanisms are not fully understood. In this study, through a genome-wide loss-of-function screen, we have identified carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) as an essential factor in a subset of MCL tumors. Our BCR signal transduction studies revealed that CEACAM1 plays a critical role in BCR signaling by orchestrating two dynamic processes. First, following BCR engagement, CEACAM1 stabilizes membrane microdomains (lipid rafts) by anchoring to the F-actin cytoskeleton through adaptor protein filamin A. Second, CEACAM1 recruits and increases the abundance of SYK in the BCR complex leading to BCR activation. These activities of CEACAM1 require its cytoplasmic tail and the N-terminal ectodomain. Considering that previous studies have extensively characterized CEACAM1 as an ITIM-bearing inhibitory receptor, our findings regarding its activating role are both surprising and context-dependent, which may have implications for BCR-targeting therapies. Main Text: