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Ferrata Storti Foundation
Haematologica 2020 Volume 105(8):2150-2163
Non-Hodgkin Lymphoma
Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
Victoria M. Smith,1,2 Anna Dietz,3 Kristina Henz,3 Daniela Bruecher,3 Ross Jackson,1,2 Lisa Kowald,3 Sjoerd J.L. van Wijk,3 Sandrine Jayne,1,2 Salvador Macip,1 Simone Fulda,3,4,5 Martin J.S. Dyer1,2 and Meike Vogler1,3
1Department of Molecular and Cell Biology, University of Leicester, Leicester, UK; 2Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK; 3Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany; 4German Cancer Research Centre (DKFZ), Heidelberg, Germany and 5German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany
ABSTRACT
The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocyt- ic 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 inves- tigated 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 seques- tration 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 involv- ing the BCL-2 family and only partially correlated with protein expression levels. Treatment with ABT-199 displaced BAX and BIM from BCL-2, sub- sequently leading to BAK activation and apoptosis. In contrast, apoptosis induced by inhibiting BCL-XL with A1331852 was associated with a dis- placement of both BAX and BAK from BCL-XL and occurred independent- ly 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 hetero- geneous response to BH3-mimetics is mediated by selective interactions between BAX, BAK and anti-apoptotic BCL-2 proteins.
Introduction
Deregulated apoptosis is a key hallmark of cancer, and high expression of anti- apoptotic proteins is frequently observed in cancer cells. Apoptosis is initiated by ligation of death receptors on the cell surface or by the release of cytochrome c into the cytosol followed by formation of the apoptosome (intrinsic apoptosis). Among the most important regulators of apoptosis is the BCL-2 protein family, which consists of both pro- and anti-apoptotic proteins.1 The pro-apoptotic BCL- 2 proteins BAX and BAK are essential for the execution of intrinsic apoptosis, as they mediate the release of cytochrome c from the mitochondrial intermembrane space. The anti-apoptotic proteins (BCL-2, BCL-XL, MCL-1, BCL-w, BCL2A1 and BCL-B) inhibit the activation of BAX and BAK, thus preventing the release of cytochrome c. BAX and BAK can be bound and inhibited directly by the anti- apoptotic BCL-2 proteins; alternatively, their activation can be inhibited by sequestration of BIM or related BCL-2 homology domain 3 (BH3)-only proteins. In this latter model, the release of BH3-only proteins from anti-apoptotic BCL-2 proteins is required in order to allow the BH3-only proteins to interact and directly activate BAX/BAK.
Correspondence:
MEIKE VOGLER
m.vogler@kinderkrebsstiftung-frankfurt.de
Received: February 26, 2019. Accepted: October 10, 2019. Pre-published: October 10, 2019.
doi:10.3324/haematol.2019.220525
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/8/2150
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