Serum IgM/Fcmr Interactions Inhibit BCR Signaling and Influence the Cinical Course of CLL

CLL cases display heterogeneous responses to B cell receptor (BCR) engagement which correlate with clinical course and survival. Typically, cases with more aggressive disease show greater activation of downstream signaling molecules, such as the kinases SYK, AKT and ERK, upon BCR engagement. The heterogeneous BCR signaling responses have been attributed to varying levels of anergy occurring as a consequence of chronic antigen engagement in the absence of T cell help. However, an alternative explanation for the anergic phenotype is that it is induced by binding of serum IgM to the high-affinity Fcμ receptor (FCMR), which is highly overexpressed on CLL cells and has been reported to physically interact with the BCR in normal murine B cells. To investigate whether binding of soluble IgM to the FCMR can affect BCR signaling, we investigated activation of downstream BCR signaling molecules in primary CLL B cells after FCMR prestimulation with monoclonal IgM or Fcμ fragment followed by BCR stimulation with polyclonal anti-light chain antibody. For 10 of the 18 cases tested, substantial reduction in the levels of phospho-SYK, phospho-AKT and phospho-ERK was observed in IgM- or Fcμ-prestimulated CLL cells consistent with FCMR stimulation inhibiting BCR signaling. Stimulation with IgM or Fcμ did not cause any appreciable change in surface IgM expression, suggesting that inhibition of BCR signaling is not caused by receptor downmodulation but rather by recruitment of negati...
Source: Blood - Category: Hematology Authors: Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research