Investigating the Role of Class-Switching on Oncogenic B Cell Receptor Signalling in Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin B cell lymphoma. It is an aggressive cancer that exhibits significant phenotypic and genetic heterogeneity. B cell receptor (BCR) signalling is a key driver of lymphoma growth and survival. However, therapies that target BCR signalling pathway only work in a subset of lymphoma patients. This suggests there are variations in how BCR signalling is harnessed across different subtypes of the disease. An understudied aspect of pathogenic BCR signalling is isotype usage. Structurally, the IgG BCR possesses a cytoplasmic immunoglobulin tail tyrosine (ITT) motif and signalling from the ITT distinguishes IgG BCR signalling from the IgM BCR, which only has a short three amino acid cytosolic domain. In physiological immune responses, class-switching from IgM to IgG enhances BCR signalling and promotes germinal centre B cell responses to antigens. In contrast, many B cell lymphomas express IgM and productive class-switching to IgG is avoided. Recent data from the Tolar lab demonstrate that class-switching from IgM to IgG reduces lymphoma cell proliferation. The lab also identified recurrent mutations in the IgG BCR intracellular tail in a subset of lymphoma patients which reverts the defect. This project aims to investigate the mechanisms through which class-switching inhibits cell proliferation, how the identified mutations promote lymphomagenesis, and whether BCR isotype usage and mutations predict disease severity and response to therapy. Better understanding of the mechanisms through which class-switching alters lymphoma pathogenesis may help to improve the therapeutic strategies for tackling this heterogenous group of cancers.