haematol.2019.220525.full.pdf (2.2 MB)
Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma.
journal contributionposted on 2020-05-05, 16:31 authored by Victoria M Smith, Anna Dietz, Kristina Henz, Daniela Bruecher, Ross Jackson, Lisa Kowald, Sjoerd JL van Wijk, Sandrine Jayne, Salvador Macip, Simone Fulda, Martin JS Dyer, Meike Vogler
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.
The authors would like to thank C. Hugenberg for expert secretarial assistance and Sandeep Dave for providing us with OCI-LY10 cells. This work has been partially supported by the Else Kröner-Fresenius-Stiftung (to MV), the Experimental Cancer Medicine Center (ECMC) Leicester and funding from the Scott Waudby Trust (to SJ and MJSD).
CitationVictoria 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,and Meike Vogler. Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma. Haematologica. 2019; 104:xxx
- AM (Accepted Manuscript)