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

Abstract 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 negative regulatory mechanism(s). Investigation of these mechanisms is still ongoing, but preliminary data suggest involvement of the phosphatases SHIP and SHP1. To investigate the impact of serum IgM/FCMR interactions on the clinical course, we correlated FCMR expression and serum IgM levels with treatment-free survival (TFS) in a large series of CLL patients (Figure 1). Cases with FCMR expression levels below median value (n=67) had a median TFS of 41 months, which was significantly shorter compared to cases with FCMR levels equal to or above median value (n=71, median TFS=132 months, P Collectively, these data show that serum IgM/FCMR interactions inhibit BCR signaling, which could at least in part explain the anergic phenotype of peripheral blood CLL cells. Along with our finding that the FCMR is downregulated by IL4 and expressed at lower levels on LN compared to PB CLL cells (Gobessi S et al, Blood 2016 128:2015), these data suggest that serum IgM/FCMR interactions are involved in regulating the intensity of the BCR signal in different compartments and consequently can influence the clinical behavior of the disease. Download : Download high-res image (261KB) Download : Download full-size image Disclosures Chen: Janssen: Research Funding; Pharmacyclics: Research Funding; ArgenX: Research Funding; Beigene: Research Funding; Verastem: Research Funding. Chiorazzi: Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.