We used biopsy specimens of primary nodal
diffuse large B-cell lymphoma (DLBCL) to investigate whether the inhibition of
caspase 8 and/or 9 apoptosis signaling pathways predicts clinical outcome. Expression levels of cellular
FLICE inhibitory protein (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 X-linked inhibitor of apoptosis (XIAP) were used to determine the status of the
caspase 9-mediated pathway. Expression of c-Flip, XIAP, Bcl-2, and
caspase 3 activity all provided prognostic information. According to these immunohistochemical parameters, inhibition of either or both
caspase signaling pathways was detected in all patients. Three groups of patients were identified, one with a
caspase 8 inhibition profile, one with
caspase 8 and 9 inhibition profiles, and one with a
caspase 9 inhibition profile.
Caspase 9 inhibition was strongly associated with poor response to
chemotherapy and usually with fatal outcome, whereas
caspase 8 inhibition was associated with excellent clinical outcome. Thus, our data strongly suggest that inhibition of the
caspase 9-mediated pathway, but not the
caspase 8-mediated pathway, is a major cause for
therapy resistance in patients with nodal DLBCL.