Unraveling the Underlying Mechanism of Bcl-2 Mutations Regulated Apoptotic Blocks in Diffuse Large B-Cell Lymphoma (Dlbcl) Patients

The BCL-2 proteins have been intensively investigated for the past few decades owing to its importance in regulating the intrinsic pathway of apoptosis. Deregulation of apoptosis is implicated in the pathogenesis of cancer and in the sensitivity of tumors to therapeutic interventions. Genome-sequencing data obtained from a large series of DLBCLs have identified frequent mutations in the translocated BCL2 gene. However, the heterogeneity of the mutation profile complicates the prediction of the functional effects of the DLBCL-specific mutations. The aim of the research is to present an integrated snapshot of recurrent missense mutations in the BCL2 gene reported in independent genomic studies and to explore the various ways these mutations could affect the binding of proteins and inhibitors leading to the activation of oncogenic pathways and drug resistance. Recognition of these pathways could have crucial ramifications for our ability to understand inter-patient heterogeneity of BCL2 mutations, thereby, providing avenues for tailored treatment of DLBCL. A considerable amount of evidence suggests the preferential clustering of mutations in the BH4 domain of the BCL-2 protein. The biochemical and structural properties of the BH4 domain enables the binding of the BH3 domain in the hydrophobic groove of the protein without being a part of the groove by stabilizing the core of the protein, thereby, maintaining the integrity of the groove. The incidence of N11Y mutation present in the BH4 domain has been reported in more than three independent studies, indicating its probable role in DLBCL pathogenesis. The impact of the N11Y mutation on the binding of a ‘BH3 mimetic’ was elucidated by molecular dynamics studies. Mutation of N11Y results in an alteration of the shape of the hydrophobic groove, subsequently changing the ligand orientation and counteracting the phenomenon of unwinding of the LB region, a crucial event observed in the wild type model. Principal component analysis captured a stretching motion of the hydrophobic groove for efficient ligand accommodation in the wild-type complex but not in the mutant model. Overall, this study unravels a probable mechanism of drug resistance induced by a BCL-2 mutation, which could be of great relevance while designing and tailoring therapeutics.