Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma.

Content Provider	Europe PMC
Author	Smith, Victoria M. Dietz, Anna Henz, Kristina Bruecher, Daniela Jackson, Ross Kowald, Lisa van Wijk, Sjoerd J.L. Jayne, Sandrine Macip, Salvador Fulda, Simone Dyer, Martin J.S. Vogler, Meike
Copyright Year	2020
Abstract	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.
ISSN	03906078
Journal	Haematologica
Volume Number	105
PubMed Central reference number	PMC7395267
Issue Number	8
PubMed reference number	31601689
e-ISSN	15928721
DOI	10.3324/haematol.2019.220525
Language	English
Publisher	Ferrata Storti Foundation
Publisher Date	2019-10-10
Access Restriction	Open
Rights License	Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: Copyright© 2020 Ferrata Storti Foundation
Content Type	Text
Resource Type	Article
Subject	Hematology