FcgRIIB and inhibitory phosphatases in B cells from CLL patients

ROMINA GAMBERALE; MARIA LAURA GABELLONI; PAULA FERNANDEZ CALOTTI; JEREMIAS GALLETI; JULIO SANCHEZ AVALOS; JORGE GEFFNER; MIRTA GIORDANO

New York, USA

Workshop; XI International Worshop on CLL; 2005

B lymphocytes express the inhibitory FcgRIIB, a low affinity receptor for the Fc portion of IgG. Although the best known function of FcgRIIB is its inhibitory capacity, which has been commonly studied in the context of BCR signaling, it was reported that murine FcgRIIB can also deliver pro-apoptotic signals upon homoaggregation. We previously showed that clonal B cells from CLL patients display high levels of FcgRIIB. Since several signaling defects have been found in CLL, the aim of this study was to evaluate the signaling capacity of FcgRIIB in CLL cells. Our result showed that FcgRIIB homoaggregation in either CLL (n=15) or tonsillar B cells (n=4) did not result in apoptosis as was reported for murine B splenocytes, suggesting that murine and human FcgRIIB trigger different signaling pathways upon homoaggregation. On the other hand, co-aggregation of FcgRIIB and BCR with anti-IgM (whole molecule) effectively diminished BCR-triggered ERK1 phosphorylation (n=6), which indicates that it is able to transduce inhibitory signals in CLL cells. As expected, this treatment resulted in tyrosine phosphorylation of a 150 KDa protein (n=5) suggesting that the inhibitory SH2-containing inositol phosphatases, SHIP, are activated during FcgRIIB and BCR co-engagement. Moreover, by western blot analysis we found that the expression of SHIP and also SH2-containing tyrosine phosphatases, SHP, was higher in CLL cells of a significant proportion of patients compared to normal B cells (n=7, p<0.05). In conclusion, we found that B cells from CLL patients: a) express functional FcgRIIB which is able to transduce inhibitory signals and b) show higher protein expression of inhibitory phosphatases compared to normal B lymphocytes. Since FcgRIIB and SHIP are able to inhibit, not only BCR-mediated, but also signals triggered by other receptors, the high expression of inhibitory phosphatases in CLL might influence leukemic cell physiology by conditioning the responses to different stimuli.