ORCID

Abstract

Introduction and aim: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell lymphoma. Therapy using Bruton’s tyrosine kinase (BTK) inhibitors has improved clinical outcomes but primary and secondary resistance to BTK inhibitor (BTKi) therapy affects more than half of MCL patients. Resistance most often arises through gene mutations in cells protected from BTKi effects within the local tissue microenvironment. This thesis develops previous work by the group identifying IRF4 as a central mediator of resistance to BTK inhibitors in MCL; the thesis aims to understand how resistance develops and to identify mechanisms to prevent or overcome BTKi resistance in MCL.Methods: Cell models of BTKi sensitivity or resistance are functionally characterised using cell biological assays and immunoblotting, and are complemented by whole exome sequencing and proteomic assays of IRF4 co-immunoprecipitation. The findings are then used to propose novel agents to overcome BTKi resistance using cell biological, microscopic and metabolic assays. Results: The work demonstrates that BTKi-resistant MCL cells fail to downregulate expression and activity of IRF4 and key signalling partners of the alternative NF-κB pathway in response to BTKi drugs in both BTKi-resistant ex vivo primary cells or cell lines with innate or acquired BTKi-resistance. The work shows also that CD40L presented by stromal cells can induce BTKi resistance in sensitive MCL cells by supporting expression of IRF4 and activity of the alternative NF-κB pathway. Genetic profiling of BTKi-resistant cell lines also identified mutations affecting negative regulators of NF-κB and WNT/β-catenin signalling pathways, while functional characterisation of IRF4 binding partners in BTKi-sensitive and resistant cells revealed involvement of IRF4 with WNT and RHO GTPase signalling pathways. Targeting the canonical WNT signalling pathway in BTKi-sensitive and resistant MCL cells using a PKF118-310 inhibitor was shown to induce a strong reduction in proliferation and a marked induction of apoptosis particularly in cells with acquired BTKi-resistance, with a potential synergistic role when combined with BTK inhibitors.Conclusion: The thesis provides novel insights into the role of IRF4 in modulating the sensitivity of MCL to BTKi drugs, particularly highlighting an importance for the alternative NF-κB and WNT signalling pathways and suggests mechanisms which could potentially overcome BTKi resistance, particularly using WNT/β-catenin inhibitors either as single agents or in combination with BTK inhibitors to overcome therapy resistance.

Keywords

Mantle cell lymphoma (MCL), Bruton's Tyrosine Kinase inhibitors, Haematology, non-Hodgkin's lymphoma, Interferon regulatory factor 4

Document Type

Thesis

Publication Date

2025

Embargo Period

2025-03-07

Creative Commons License

Creative Commons Attribution-NonCommercial 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

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