Profiling of Caspase Signaling Pathways Predicts Clinical Response to Chemotherapy in Diffuse Large B-Cell Lymphomas.

Abstract

Disruption of the apoptosis signaling cascade is a probable cause for resistance to chemotherapy in patients with diffuse large B-cell lymphomas (DLBCL). We investigated whether inhibition of either or both caspase 8 and 9 apoptosis signaling pathways in biopsy specimens of primary nodal (DLBCL) predicts clinical outcome. Expression levels of c-Flip and numbers of active caspase 3 positive lymphoma cells were used to determine the status of the caspase 8 mediated pathway. Expression levels of Bcl-2 and XIAP were used to determine the status of the caspase 9 mediated pathway. Expression of c-FLIP, XIAP and Bcl-2 and caspase 3 activity all provided prognostic information. According to these immuno-histochemical parameters, inhibition of either or both caspase signaling pathways was detected in all cases. Three groups were identified: one with a caspase 8 inhibition profile, one with a caspase 8 and 9 inhibition profile and one with a caspase 9 inhibition profile. The caspase 9 inhibition profile was strongly associated with a poor response to chemotherapy and a usually fatal outcome, whereas the caspase 8 inhibition profile was associated with excellent clinical outcome. Functional analysis of apoptosis sensitivity confirmed that apoptosis profile was directly related to chemotherapy sensitivity. Thus, our data strongly suggest that inhibition of the caspase 9 and not the caspase 8 mediated pathway is a major cause for therapy resistance in patients with nodal DLBCL.