Overcoming receptor proximal mutations in DLBCL through systems modelling

B Cell Receptors react to antigen stimulus, transducing signal to NFkB, and triggering an immune response. Inoue et al[1] modelled this pathway in health. B Cell Lymphoma frequently displays chronically active NFkB caused by mutations in this receptor-proximal signalling pathway. We sought to mechanistically investigate the impact of mutation on BCR signalling and predict therapeutic interventions.A common mutation in CARD11 was modelled by modifying parameters corresponding with experimentally-identified effects of this mutation. In response to stimulation, the mutant CARD11 model is significantly more active; and switches to chronically active when the basal BCR signal exceeds a very low level (<1%). This low activation threshold suggests that the CARD11 mutation alone may be sufficient for chronic NFkB activation.By performing parameter sensitivity analysis on the mutant model; the parameters with the greatest influence on NFkB were identified. This approach identified several IKK reactions which have been the target of much therapeutic development. Unfortunately, due to the ubiquitous expression of NFkB and lack of specificity, development of these inhibitors has generally stalled. This work is motivating ongoing expansion of the model to include the Cheng et al 2015 model of Toll Like Receptor signalling, to increase the number of mutable/druggable targets.