Exploring the role of Bcl-2 family members & B-cell targeted therapies From CLL to B-IMDs

This thesis focused on investigating crucial signaling pathways within the microenvironment of chronic lymphocytic leukemia (CLL). The aim was to examine the potential of combination therapies in addressing drug resistance associated with the microenvironment. Furthermore, our objective was to understand the role of the intrinsic apoptosis pathway in both CLL and in B-cell immune-mediated diseases (B-IMDs), including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
We specifically investigated the correlation between expression levels of BCL-2 family members in CLL and SLE/RA and their clinical responses. Additionally, we explored the potential benefits of targeting BCL-2 family members in autoimmune diseases to enhance treatment approaches.
Our findings highlight the microenvironment's strong impact on CLL treatment resistance via multiple pathways. We found a CD40-TLR9 interaction, disrupted by ibrutinib, emphasizing the need to target key pathways together. Time-limited combination therapies reduce resistance risks and offer reinitiation potential. Although the efficacy of combination therapy in B-IMDs remains unexplored, comprehensive study of the BCL-2 family may offer insights for future treatments. Based on our CLL findings, exploring BTK or MALT1 inhibitors with BH3 mimetics in B-IMDs could potentially control and regulate the imbalanced adaptive immune system in B-IMDs.