Rel a Is a Novel Prognostic Marker in CLL That Is Independent of V_H Gene Mutation Status, CD38 Expression and ZAP-70 Expression

We recently demonstrated that the NF-kB subunit Rel A is associated with in vitro survival and clinical disease progression in CLL. We therefore hypothesized that Rel A would have prognostic significance in this disease. Rel A DNA binding was quantified in nuclear extracts derived from 131 unselected CLL patient samples using a quantitative DNA binding ELISA-based method. We tested the ability of Rel A to predict for the requirement for treatment and survival and compared our findings with other established prognostic markers. Rel A DNA binding was strongly associated with advanced Binet stage (P<0.0001) but did not correlate with IgV_H mutation status (P = 0.25), CD38 expression (P = 0.87) or ZAP-70 expression (P = 0.55). It was predictive of time to first treatment (P = 0.02) and time to subsequent treatment (P = 0.0001). In addition, Rel A was the most predictive marker of survival both from date of diagnosis (hazard ratio 9.1, P = 0.01) and date of entry into the study (hazard ratio 3.9, P = 0.05) and retained prognostic significance in multivariate analysis for both time to first treatment and overall survival in the presence of Binet stage, IgV_H mutation status, CD38 and ZAP-70. Take together our data shows that Rel A is an independent prognostic marker of survival in CLL and appears to have the unique capacity to predict the duration of response to therapy. Prospective assessment of Rel A as a marker of clinical outcome and as a therapeutic target is now clearly warranted.