Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma diagnosis. Targeted therapeutics originally focused on the cell-of-origin hypothesis, which divides DLBCL into subtypes based on the origin of oncogenic cells. However, newer classifications point to a wider diversity of subtypes and one gene that is mutated in approximately 5% of newly diagnosed DLBCL encodes the BCL10 protein. BCL10 associates with CARD11 and MALT1 to activate downstream oncogenic pathways such as the canonical NF-kB and JNK. The mechanisms by which BCL10 mutations promote lymphomagenesis and drug resistance are poorly understood. We hypothesize that BCL10 mutations promote oncogenesis and contribute to drug resistance through activation of NF-kB signaling. Methods: We used a luciferase dual reporter assay to probe NF-kB activity in 293T cells with wild-type or mutant BCL10. Overexpression of two recurrent mutations was performed using a doxycycline-inducible system in DLBCL cell lines and Western Blot was used to identify changes in signaling pathways. Next, we used a human phosphokinase array to determine the profile of phosphorylated proteins and RNA sequencing to understand changes in gene expression. Results:Our data indicate upregulation of both canonical and noncanonical NF-kB pathways and increased MALT1 activity. Additionally, the phosphokinase array and RNA sequencing data showed upregulated ERK signaling and activation of cytokine-mediated signaling. Conclusion: Our results demonstrate mechanisms through which BCL10 mutations may promote lymphomagenesis and identify potential drug targets. Further analysis of targetable signaling pathways, including ERK and cytokine signaling, are underway.
