Spatial Organization and Early Signaling of the B-Cell Receptor in CLL

Immunoglobulin G (IgG) class-switched mutated chronic lymphocytic leukemia (M-CLL) likely represents the same disease as IgM M-CLL rather than a different biological and/or clinical entity, according to a recent study  (Front Immunol. 2022;13:953660. doi:10.3389/fimmu.2022.953660).

Yamit Shorer Arbel, Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel, and colleagues wrote, “Most chronic lymphocytic leukemia (CLL) clones express B-cell receptors (BcR) of both IgM/IgD isotypes; however, 5%–10% of CLL cases express isotype-switched immunoglobulin G (IgG),” adding, “The early signaling and spatial patterning of the various BcRs at steady state and after activation are still fully unresolved.” 

Researchers obtained cells from peripheral blood samples donated by patients fulfilling the standard criteria for CLL after signing informed consent approved by the Tel-Aviv SAkuraSky Medical’s Institutional Review Board according to the Helsinki Accords.

They found that higher expression of the BcR signalosome elements and a more robust constitutive cell-intrinsic proximal BcR signaling in CLL with unmutated IGHV expressing IgM isotype (IgM U-CLL), compared with IGHV-mutated CLL (M-CLL) expressing either IgM or IgG isotypes.

Researchers also noted that study findings demonstrate distinct differences in the early BcR signalosome, signaling responses, and spatial organization between CLL immunogenetic subtypes and in particular, show that the IgG class-switched M-CLL is biologically closely related to IgM M-CLL and has a comparable favorable clinical outcome.

The authors wrote,“We report fundamental differences in the basal composition, biochemical status, and spatial organization of the BcR in the three examined immunogenetic CLL subtypes that correlate with their clinical behavior, adding, “Although U-CLL shows a more robust constitutive BcR pathway activation and a better responsiveness to BcR engagement, our data suggest that the BcR pathway is also a therapeutic target in IgG CLL.”

“We provide evidence that class-switched M-CLL likely represents the same disease as IgM M-CLL rather than a different biological and/or clinical entity,” the authors concluded.