Bob.1 Blocks a SYK Protein Degradation Pathway in Mice That Develop Chronic Graft Versus Host Disease Manifestations

After elucidating a role for aberrant B Cell Receptor (BCR) signaling in chronic graft versus host disease (cGVHD) (Allen et al, Blood. 2014;123:2108), we showed that the proximal BCR molecule SYK is a viable therapeutic target in mice and patients (Flynn et al, Blood 2015; 125:4085. Poe et al, JCI Insight. 2018;3:e122430. NCT02611063). Increased SYK protein levels associate with enhance phosphorylation of SYK activation sites, leading to immediate BCR responsiveness in cGVHD. In mice that develop cGVHD manifestations after allogeneic bone marrow transplantation (BMT), BCR responsiveness is promoted by B Cell Activating Factor (BAFF) (Jia et al, Blood. 2021;137:2544). Instead of SYK protein levels decreasing upon engagement with surrogate antigen to regulate excessive BCR-signaling, SYK protein was maintained when BAFF and alloantigen were present. In the present study, we address a potential molecular mechanism underpinning SYK protein maintenance in cGVHD B cells.