Expression of cFLIP in B cells is essential for diffuse large B-cell lymphoma pathogenesis.

Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignant disease that remains a major clinical challenge, as relapsed and refractory disease is difficult to treat. Apoptosis evasion is a major feature of DLBCL. However, while the suppression of intrinsic apoptosis has long been recognized as a lymphoma-promoting event, the role of extrinsic apoptosis has remained poorly defined. In this study, we demonstrated at the genetic level that expression of cellular Fas-associated death domain protein-like IL-1β-converting enzyme-inhibitory protein (cFLIP), the most crucial, non-redundant inhibitor of extrinsic apoptosis, in B cells is necessary for the development of DLBCL in an autochthonous murine model. Indeed, B-cell-specific deletion of Cflar, the gene encoding for cFLIP, prevented lymphomagenesis mediated by oncogenic Myd88 and overexpression of BCL2. In human lymphoma cells, we showed that the absence of cFLIP sensitized activated B-cell-like (ABC)- but not germinal center B-cell-like (GCB)-DLBCL subtype cells to TRAIL- or lipopolysaccharide-induced, caspase-8-mediated apoptosis. Furthermore, we unveiled a cell death-independent role of cFLIP in the suppression of proinflammatory cytokines at the transcriptional level, selectively in the ABC subtype. These results indicate that the suppression of intrinsic apoptosis can support lymphomagenesis only if extrinsic apoptosis is properly controlled. Moreover, licensing extrinsic apoptosis through CFLAR deletion can efficiently promote death in DLBCL cells, despite the suppression of the intrinsic pathway. Overall, these data provide a rationale for the development of cFLIP inhibitors for the treatment of ABC-DLBCL and possibly other hematological cancers.