Expression of cFLIP in B cells is essential for diffuse large B-cell lymphoma pathogenesis
Abstract
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.
Article Details
Authors (31)
Kristie Tanavura Bariboloka
University of Cologne, Cologne, Germany
Santiago Serrano-Saenz
University of Cologne, Cologne, Germany
Deniz Pinar Savcigil
University of Cologne, Cologne, Germany
Sarah Spoeck
Medical University of Innsbruck, Innsbruck, Austria
Rebecca E. Poss
University Hospital Frankfurt am Main, Frankfurt am Main, Germany
Luca D. Schreurs
University of Cologne, Cologne, Germany
Jens Löber
Charité - University Medical Center Berlin, Berlin, Germany
Nazli Serin
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Justinas Valiulis
University of Cologne, Cologne, Germany
Kalvin Nugraha
University of Lausanne, Lausanne, Switzerland
Giulia Gangarossa
University of Florence, Florence, Italy
Anna Lütz
Moritz Reese
Sebastian Klein
Julius C. Enssle
Goethe University Frankfurt, University Hospital, Frankfurt, Germany
Reinhard Büttner
Hamid Kashkar
Institute for Molecular Immunology, CECAD Research Center, University of Cologne, cologne, Germany
Martin Peifer
Björn Chapuy
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Gero Knittel
1University Hospital Essen
Verena Labi
Innsbruck Medical University, Innsbruck, Austria
Andreas Villunger
Phuong-Hien Nguyen
University of Cologne
Sebastian Scheich
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Thomas Oellerich
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Henning Walczak
Ruth Flümann
University Hospital Cologne, Cologne, Germany
Ron D Jachimowicz
University Hospital of Cologne, Germany, Cologne, Germany
Michael J Hallek
University of Cologne, Cologne, Germany
Hans Christian Reinhardt
Alessandro Annibaldi