Drivers of B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common GC-derived lymphoma in adults, and is characterised by clinical heterogeneity with respect to survival and response to therapy. DLBCL B cells exhibit aberrant expression of the Forkhead box-P1 (FOXP1) transcription factor, which further contributes to the clinical behaviour of DLBCL and resistance to treatment. As a result, understanding the molecular impact of FOXP1 deregulation in DLBCL is paramount for patient stratification and correct diagnosis. The primary objective of the EU-funded LYMFOXP1 (Role of the transcription factor FOXP1 in B cell function and lymphomagenesis) project was to explore the role of FOXP1 as a transcriptional regulator of mature B cell function and lymphomagenesis. Overall, they wished to identify novel transcriptional targets of FOXP1 deregulation in B cells and design novel potential therapeutic strategies to target them. Particular emphasis was given to NF-kB hyperactivation and the incompletely understood mechanisms of ongoing genomic instability seen in DLBCL. In this context, scientists generated mice that incorporated several selected genetic alterations recurrently found in human DLBCL. They undertook survival analysis and molecular and genetic characterisation of tumours, and compared this to genetic and epigenetic data obtained from human samples. Overall, the FOXP1-positive DLBCL mouse model represented a valid novel preclinical model to better understand the pathogenic mechanisms that lead to B-cell lymphoma. Using this model, researchers identified novel biomarkers and various deregulated molecular pathways in DLBCL that have the potential to be exploited therapeutically. Furthermore, the novel mechanism of FOXP1 contribution to genomic instability opens up new research and treatment avenues.
Keywords
B-cell lymphoma, FOXP1, LYMFOXP1, NF-kB, genomic instability
