RT Journal Article
SR Electronic
T1 Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
JF Haematologica
JO Haematologica
FD Ferrata Storti Foundation
SP haematol.2019.220525
DO 10.3324/haematol.2019.220525
A1 Smith, Victoria M.
A1 Dietz, Anna
A1 Henz, Kristina
A1 Bruecher, Daniela
A1 Jackson, Ross
A1 Kowald, Lisa
A1 van Wijk, Sjoerd J.L.
A1 Jayne, Sandrine
A1 Macip, Salvador
A1 Fulda, Simone
A1 Dyer, Martin J.S.
A1 Vogler, Meike
YR 2019
UL http://www.haematologica.org/content/early/2019/10/07/haematol.2019.220525.abstract
AB The BCL-2 specific inhibitor, venetoclax/ABT-199 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, 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 activity. We have investigated the roles of the BCL-2 proteins in diffuse large B-cell lymphoma cells using a panel of specific BCL-2 Homology 3 mimetics and identified subgroups of diffuse large B-cell lymphoma cells that exhibited marked and specific dependency on either BCL-2, BCL-XL or MCL-1 for survival. Dependency was associated with a sequestration of the pro-apoptotic proteins BIM, BAX and BAK selectively by the specific anti-apoptotic BCL-2 protein that was important for cellular survival. Sensitivity to BCL-2 Homology 3 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, leading subsequently 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 diffuse large B-cell lymphoma, the heterogeneous response to BCL-2 Homology 3 mimetics is mediated by selective interactions between BAX, BAK and anti-apoptotic BCL-2 proteins.