The role of Immunoglobulin class-switching in oncogenic B cell receptor signalling in lymphoma

Primary supervisor: Pavel Tolar, UCL

Secondary supervisor: Jessica Okosun, Queen Mary University of London

Project

Non-Hodgkin B-cell lymphomas are amongst the most common haematopoietic malignancies, and although therapies are available, up to 40% of patients develop a refractory or relapsing disease that can be fatal. In recent years, B cell receptor (BCR) signalling has been identified as an important driver of lymphoma cell growth, suggesting that targeting the BCR pharmacologically may be used as a therapy [1,2]. However, BCR-targeting therapies have not fulfilled their clinical potential, primarily because of the enormous genetic diversity of the disease encompassing distinct mechanisms of BCR activation and downstream signalling pathways [3]. A poorly understood aspect of the heterogeneity relates to the isotype of the BCR, with most B cell lymphomas expressing the IgM and genetically preventing class-switching to IgG [4]. This suggests that unlike physiological B cell responses, where class-switching to IgG promotes B cell expansion and antibody production, class switching supresses lymphoma pathogenesis. Elucidating the putative tumour suppressive mechanisms downstream of the IgG BCR could reveal novel therapeutic options and help identify malignant mechanisms that sometimes subvert this process and cause progressive disease despite expression of the IgG BCR.

The main aim of the PhD project is to understand the role of class switching in the BCR-driven pathogenesis of B cell lymphomas on the molecular level. In recent work, we identified recurrent mutations in the IgG-expressing diffuse large B cell lymphomas and follicular lymphomas affecting the intracellular tail of the IgG BCR. Preliminary experiments indicate that class-switching from IgM to IgG is detrimental to lymphoma cell proliferation but is rescued by these IgG BCR mutations. We hypothesise that these mutations promote oncogenic BCR signalling and can help with patient stratification for therapy. The candidate will investigate the molecular mechanism by introducing these mutations into B lymphoma models in vitro and in vivo and investigating their effects on BCR kinase signalling pathways and lymphoma growth. The identified mechanisms will be validated in patient samples and tested for predicting response to BCR-targeted therapy in preclinical models, such as cell lines and synthetic tumours. A number of molecular and genetic tools, animal models, as well as bioinformatic expertise, are available for the project in the host labs.

Candidate background

We are looking for a motivated candidate with a strong background in biomedicine (e.g. molecular genetics, cancer biology, or immunology) and a keen interest in bioinformatics. The candidate will learn to model lymphoma mutations using CRISPR, analyse signalling pathways by flow cytometry and biochemistry, analyse lymphoma development in mouse models, and carry out bioinformatic analyses of human lymphoma samples.

Potential Research Placements

1. Dinis Calado, Francis Crick Institute
2. Franca Fraternali, Institute of Structural and Molecular Biology, UCL
3. Daniel Hodson, Stem Cell Institute, University of Cambridge

References

1. Davis, R. E. et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 463, 88-92 (2010).
2. Young, R. M. et al. Taming the Heterogeneity of Aggressive Lymphomas for Precision Therapy. Annu Rev Cancer Biology 3, 1-27 (2018).
3. Young, R. M., Shaffer, A. L., Phelan, J. D. & Staudt, L. M. B-cell receptor signaling in diffuse large B-cell lymphoma. Seminars in hematology 52, 77-85 (2015).
4. Lenz, G. et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. The Journal of experimental medicine 204, 633-643 (2007).