The enigma of immunoglobulin class-switching in B cell 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 their prognosis and therapy are complicated by molecular heterogeneity. Similarly to normal B cells, B cell lymphomas are often addicted to B cell receptor (BCR) signalling, which drives cell proliferation and survival. BCR signalling is thus a potential target for therapy (1). However, different molecular subsets of lymphoma use distinct and sometimes poorly understood branches of BCR signalling pathways (e.g. NFκB or PI3-kinase pathways), making BCR-targeted therapies challenging and so far not universally effective (2). Interestingly, B cell lymphomas express preferentially the IgM isotype of the BCR and genetically prevent class-switching to IgG (3). The preference for IgM BCR has never been explained but suggests that unlike physiological B cell responses, where class-switching promotes B cell expansion and antibody production, class switching in lymphoma is suppressive. Identifying the tumour suppressive mechanisms downstream of the IgG BCR could reveal novel therapeutic options and explain how some lymphoma subsets evade such suppression and cause progressive disease despite expressing 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. 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 IgG BCR mutations. We hypothesise that the IgG BCR signalling tail inhibits oncogenic BCR signalling. The student candidate will test this idea by introducing these mutations into B lymphoma models and investigating their effects on BCR kinase signalling pathways. 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, synthetic tumours and mouse models. A number of molecular and genetic tools, as well as bioinformatic analyses of patient data, 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, and carry out bioinformatic analyses of lymphoma transcriptomics and DNA mutations.

Potential Research Placements

1. Dinis Calado, Francis Crick Institute
2. Franca Fraternali, King’s College London
3. Francesca Ciccarelli, King’s College London/ Francis Crick Institute

References

1. 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).
2. Chapuy, B. et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nature Medicine 24, 679 – 690 (2018).
3. 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).