Expression of cFLIP is necessary for diffuse large B cell lymphoma pathogenesis

Diffuse large B cell lymphoma (DLBCL) is a highly heterogenous 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. Here, we demonstrated at the genetic level that expression of cFLIP, the most crucial, non-redundant inhibitor of extrinsic apoptosis, in B cells is necessary for the development of diffuse large B cell lymphoma (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 sensitizes ABC- but not GCB DLBCL subtype cells to TRAIL- or LPS-induced, Caspase-8-mediated apoptosis. Furthermore, we unveiled a cell death-independent role of cFLIP in the suppression of pro-inflammatory 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 via cFLIP deletion can efficiently promote the death of DLBCL cells despite the suppression of the intrinsic pathway. Overall, these data provide the rationale for the development of cFLIP inhibitors for the treatment of ABC DLBCL and possibly other haematological cancers.