פגישות חוקרים "בראש חוקר" - 13 ליוני 2012

Divergence in CD19-mediated signaling unfolds intra-clonal diversity in chronic lymphocytic leukemia which correlates with disease progression

Purpose: Emerging data on intra-clonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. We have analyzed intra-clonal diversity in response to CD19 engagement in primary CLL cells.
Experimental design: CLL cells responded to CD19 engagement by rapid aggregation evaluated by a non-conventional flow cytometric analysis. Specific sub-populations identified according to these responses were characterized, and CD19 signaling modes were evaluated. Then, the clinical significance of the CLL sub-populations composition was determined. 
Results: Monoclonal anti-CD19 antibody rapidly induced cellular aggregation of CLL cells identified as a high side scatter lymphoid population (HSLP). The induction of cellular aggregation via CD19 was completely abrogated by disruption of the cholesterol-rich plasma membrane rafts, but minimally affected by various signaling inhibitors. The CLL sub-population which responded to CD19 clustering expressed higher mRNA levels of c-myc, exhibited distinct morphological features, and was abolished in rituximab-treated patients. CLL patients with more than 20% of HSLP had a shorter median time to treatment compared to patients with less HSLP, with no correlation to ZAP-70 expression.
Conclusions: Intra-clonal diversity for CD19-mediated cellular aggregation in CLL correlates with time to treatment initiation. The heterogeneous CD19 response may reflect differences in the juxta-membrane signaling patterns within the CLL clone. Responses to therapeutics vary between sub-populations of the CLL clone