Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
Victoria M. Smith,
Anna Dietz,
Kristina Henz,
Daniela Bruecher,
Ross Jackson,
Lisa Kowald,
Sjoerd J.L. van Wijk,
Sandrine Jayne,
Salvador Macip,
Simone Fulda,
Martin J.S. Dyer,
Meike Vogler
Affiliations
Victoria M. Smith
Department of Molecular and Cell Biology, University of Leicester, Leicester, UK;Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK
Anna Dietz
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany
Kristina Henz
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany
Daniela Bruecher
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany
Ross Jackson
Department of Molecular and Cell Biology, University of Leicester, Leicester, UK;Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK
Lisa Kowald
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany
Sjoerd J.L. van Wijk
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany
Sandrine Jayne
Department of Molecular and Cell Biology, University of Leicester, Leicester, UK;Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK
Salvador Macip
Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
Simone Fulda
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany;German Cancer Research Centre (DKFZ), Heidelberg, Germany;German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany
Martin J.S. Dyer
Department of Molecular and Cell Biology, University of Leicester, Leicester, UK;Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK
Meike Vogler
Department of Molecular and Cell Biology, University of Leicester, Leicester, UK;Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany
The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma (DLBCL), despite high level expression of BCL-2 in over 40% of cases, indicating that co-expression of related anti-apoptotic BCL-2 family proteins may limit the activity of ABT-199. We have investigated the roles of BCL-2 proteins in DLBCL cells using a panel of specific BCL-2 homology 3 (BH3)-mimetics and identified subgroups of these cells that exhibited marked and specific dependency on either BCL-2, BCL-XL or MCL-1 for survival. Dependency was associated with selective sequestration of the pro-apoptotic proteins BIM, BAX and BAK by the specific anti-apoptotic BCL-2 protein which was important for cellular survival. Sensitivity to BH3-mimetics was independent of genetic alterations involving the BCL-2 family and only partially correlated with protein expression levels. Treatment with ABT-199 displaced BAX and BIM from BCL-2, subsequently leading to BAK activation and apoptosis. In contrast, apoptosis induced by inhibiting BCL-XL with A1331852 was associated with a displacement of both BAX and BAK from BCL-XL and occurred independently of BIM. Finally, the MCL-1 inhibitor S63845 induced mainly BAX-dependent apoptosis mediated by a displacement of BAK, BIM and NOXA from MCL-1. In conclusion, our study indicates that in DLBCL, the heterogeneous response to BH3-mimetics is mediated by selective interactions between BAX, BAK and anti-apoptotic BCL-2 proteins.
