A recent study published in Science has uncovered new insights into the mechanisms underlying poor outcomes in Diffuse Large B Cell Lymphomas (DLBCLs) and the role of BTG1 mutations in these outcomes. DLBCLs are aggressive malignancies that are difficult to treat, with about 40% of patients failing to respond or becoming refractory to treatment. However, the mechanisms that mediate these poor outcomes are not well understood.
The study investigated the role of BTG1 mutations in DLBCLs, which are a type of B cell lymphoma that originate from specialized B cells called germinal centre (GC) B cells. During the adaptive immune response, GC B cells undergo iterative rounds of natural selection to generate high-affinity B cell receptors. This process involves somatic hypermutation and clonal expansion of GC B cells and is dependent on B cells competing to receive positive selection signals from T follicular helper (TFH) cells.
The researchers used a mouse model to show that the most common BTG1 mutation (BTG1Q36H) impairs the function of BTG1 and causes an increase in MYC-dependent growth programs. This leads to a higher rate of malignant transformation in GC B cells. They found that the mutant protein is associated with mRNAs for MYC and MYC target genes, which resulted in a lower threshold for BTG1 mutant cells to respond to TFH cell positive selection signals. This accelerated response to TFH cells resulted in the formation of highly aggressive lymphomas in the mouse model.
In addition to the findings in the mouse model, the study also found that BTG1 mutations were associated with poor clinical outcomes in patients with DLBCL. The team behind this study found that BTG1 mutations scored as strong genetic DLBCL drivers and independently associated with significantly inferior clinical outcomes.
These findings reveal that BTG1 serves as a critical gatekeeper in controlling the selection of GC B cells during the adaptive immune response and that targeting BTG1 function could be a potential therapeutic strategy for DLBCL. The study also highlights the fragility of the constraints required to prevent competing B cells from recalling features of uncontrolled natural selection among unicellular organisms and the fine-tuned balance between protection against infection and cancer risk.
Overall, this study provides new insights into the mechanisms underlying poor outcomes in DLBCLs and the role of BTG1 mutations in these outcomes. These findings could also have implications for the treatment of other diseases and the identification of new therapeutic targets.