Stress Induced Signaling Pathways in Burkitt’s Lymphoma Play Novel Mechanisms in Fate Determination and Pathogenesis of Germinal Center-Derived B-Lymphomas

Abstract B cell receptor signaling, NF-κB signaling, BCL6 and p53 regulation are essential for germinal center (GC) B cell fate. Dysregulation of these pathways drives the pathogenesis and treatment resistance of GC-derived B-lymphomas (GCDBL). To explore how these pathways affect GCDBL fate and pathogenesis, we treated Raji cells (a GCDBL and Burkitt’s lymphoma) with mild hydroxyurea (HU) to simulate genotoxic stress encountered by GC B cells. Genome-wide mapping of histone H3K4me3 and p53 target analysis in HU-treated Raji cells combined with transcriptome analysis of human tonsil GC B cells identified ATAD2B (a p53 target) as differentially expressed. We found that p53 suppresses ATAD2B and ATAD2 , while ATAD2 and BCL6 transcripts positively correlate in DLBCLs, suggesting that p53 regulates BCL6 in GC B cells via ATAD2 suppression. We propose that p53 regulation of BCL6 quality assures GC B cells before GC exit. Unlike BCL6 suppression of IFN-γ and NF-κB signaling in GC B cells, we identified IFNGR1 as a loosely bound BCL6 target and observed loss of BCL6 regulation on genes encoding inhibitory subunits of NF-κB signaling in B-lymphoma treated with a Bruton tyrosine kinase (BTK) inhibitor. These adaptations, alongside with prevalent genetic inactivation of NF-κB inhibitory genes in DLBLCs, likely contribute to DLBCL pathogenesis and therapy resistance. Our findings highlight the pivotal role of the p53-BCL6 axis in GC B cell fate and its dysregulation in DLBCL pathogenesis and chemoresistance. Key Highlights Genes induced in human Burkitt’s lymphoma under genotoxic stress are largely independent of histone H3K4me3 marks at transcriptional start sites (TSS). Loss of BCL6 regulation on genes encoding components of IFN-γ signaling is associated with reduced survival and the pathogenesis of DLBCL. Inactivating mutations in genes encoding components of the NF-κB inhibitory subunit serve as an adaptation for DLBCL pathogenesis. BCL6 expression is correlated with ATAD2 overexpression in DLBCL and solid tumors.