EXPLORING THE SENSITIVITY OF MANTLE CELL LYMPHOMA TO INHIBITORS OF BRUTON’S TYROSINE KINASE Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma which responds poorly to conventional chemotherapy. Inhibitors of Bruton’s tyrosine kinase (BTKi) have shown a significant clinical effect; despite this success however, approximately one third of MCL patients have primary resistance to the drug, and patients who initially respond to treatment frequently acquire secondary resistance with aggressive relapse of the disease. The purpose of this study was to understand how BTKi-resistance or sensitivity is mediated, aiming to identify new targets for therapy or predictive biomarkers of response. Combining a range of cell culture, biochemical and molecular techniques, the work presented describes the development of in vitro models of MCL with different sensitivity or resistance to BTKi. These models identify distinct functional and signalling responses of sensitive or resistant cell lines during BTKi treatment in the presence or absence of stromal cell support. The REC-1 cell line demonstrated reduced survival, proliferation, inhibition of BTK and ERK signalling, and downregulation of IRF4 expression in response to BTK inhibition. In contrast, resistant cell lines (G519, JEKO-1 and JVM2) or REC-1 cells with acquired resistance to BTKi did not downregulate IRF4. The stromal microenvironment also supported BTKi resistance and opposed IRF4 downregulation. These findings were reproduced using ex vivo primary MCL cells taken before and during clinical BTKi therapy, identifying IRF4 as a potential mediator and biomarker of BTKi treatment sensitivity or resistance in a clinical setting. Further detailed assessment of IRF4 protein interactions using molecular and proteomic approaches in BTKi sensitive cells identified a novel potential association with proteins involved in mitochondrial function that may be involved in resistance to treatment with BTKi. Further investigation of these interactions may indicate novel targets for the design of therapeutic combinations which can overcome BTKi resistance in MCL.

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