Insights In Bcl-2 Dependence In Diffuse Large B-Cell Lymphomas -Two Sides Of The Same Anti-Apoptotic Coin

We aim to get a better insight in the pathology of diffuse large B-cell lymphoma (DLBCL) on the cellular and molecular level. To do this, we studied two different aspects of the anti-apoptotic role of the protein B-cell lymphoma-2 (Bcl-2), a protein involved in cell fate decisions.Typically, Bcl-2 prevents cell death by sequestering pro-apoptotic proteins via a hydrophobic groove on its surface. This working mechanism of Bcl-2 can be blocked by BH3 mimetics, small molecules that bind the hydrophobic groove and prevent capturing of pro-apoptotic proteins by Bcl-2. Venetoclax is a Bcl-2-specific BH3 mimetic and is able to kill cancer cells that rely on Bcl-2 for their survival. It is used in the clinic to treat relapsed patients suffering from chronic lymphocytic leukaemia. Despite its success, resistance against venetoclax has been reported in the clinic. Thus, a first aspect we wanted to study was venetoclax resistance in DLBCL cell lines, comparing a naïve cell line with a cell line previously exposed and rendered resistant to venetoclax. We report that venetoclax resistance in this specific instance occurred through upregulation of another anti-apoptotic protein from the Bcl-2-protein family: Bcl-XL.Apart from its canonical role, Bcl-2 exerts many "moonlighting" functions. One of these is its control over apoptosis by inhibiting Ca2+ release from the endoplasmic reticulum through the inositol 1,4,5-trisphosphate receptor (IP3R). As opposed to its classic anti-apoptotic function, the hydrophobic groove does not play a role in the Bcl-2-IP3R interaction. It is rather the BH4 domain of Bcl-2 that prevents IP3R-mediated Ca2+ release. Bcl-2-IP3R disruptor-2 (BIRD-2) is a decoy peptide that can break the Bcl-2-IP3R interaction, thereby killing cancer cells. However, its downstream signalling effects were not well understood. We observed that BIRD-2 triggers mitochondrial Ca2+ uptake and mitochondrial permeability transition pore opening, causing caspase activation and cell death in DLBCL cell lines.In this thesis, we studied both resistance towards venetoclax and downstream signalling triggered by peptide-mediated disruption of the IP3R-Bcl-2 interaction in DLBCL. We gained insight in the importance of both targeting the canonical role of Bcl-2 and targeting the non-canonical Bcl-2-IP3R interaction. We hope these results contribute to further exploitation of Bcl-2-centered therapies in DLBCL.

Jaar van publicatie:2020

Toegankelijkheid:Open