CD49d governs immune synapse formation through actin rearrangements and synchronizes BCR signaling in CLL

CD49d-loss-related F-actin polymerization and transcriptomic defects in cytoskeleton-associated pathways were found in mouse and human. The requirement of CD49d for engraftment and actin organization could be recapitulated in a second murine model with highly aggressive transformed CLL. RNAseq analyses and kinome profiling revealed impaired antigen responsiveness due to kinase transcription and activity shifts in CD49d-deficient murine leukemic cells, recapitulated in human while applying several human BCR signatures.

Finally, in human CLL expressing low CD49d, actin organization was deregulated, along with a desynchronization of Syk and PLCgamma activation. In summary, our findings establish CD49d as a key regulator of BCR functionality, linking integrin signaling to cytoskeletal dynamics and antigen responsiveness in CLL.