Cancer B-Cell Group
Cancer B-Cell Group

Research themes

Learn about the themes our research focuses on.

Lymphoma

Our research in this area focuses on the study of tumour glycans on the surface immunoglobulin (sIg).

The acquisition of N-glycosylation sites in the sIg variable region by somatic hypermutation is a tumour-specific event of some germinal centre-derived lymphomas including follicular lymphoma (FL), a subset of the most aggressive diffuse large B-cell lymphomas (DLBCL) and Burkitt lymphomas (BL). In FL the acquired N-glycosylation sites (AGS) are selected in the antigen-binding sites of the tumour sIg.

We have developed further knowledge around this tumour-specific phenomenon, discovering that in FL the sIg sites are occupied by oligomannose-type glycans (sIg-Mann). SIg-Mann can specifically interact with the lectin DC-SIGN, expressed on macrophages and follicular dendritic cells of the tumour lymph node. We have hypothesised that the interaction between DC-SIGN and sIg-Mann induces signals in the tumour B cells, favouring cell retention, growth and survival in the tissue. We discovered that a subset of DLBCL, genetically related to FL, carries AGS in the sIg and that, when located into the antigen binding site, AGS are also occupied by oligomannose-type glycans, thus allowing interaction with DC-SIGN.

Our current projects focus on:

  • better understanding the consequences of sIg-Mann engagement by DC-SIGN at molecular level through flow cytometry, immunoblotting, confocal microscopy, super-resolution microscopy, spatial biology
  • further dissecting the distinct glycan structures that occupy the AGS depending on site location and cell of origin by bioinformatic and glycobiology analyses, including site-specific mass spectrometry and crystallography.
  • the development of anti-DC-SIGN antibodies specific for the carbohydrate recognition domain of DC-SIGN able to block the DC-SIGN:sIg-Mann interaction, to be used in the clinic for therapeutic purposes.

Chronic lymphocytic leukaemia (CLL)

We work to understand how the structure and function of the tumour surface immunoglobulin (sIg) affects tumour behaviour. Analysis of the sIg has led to transformations in how we assess and treat patients.

Our centre was the first to indicate that CLL should be classified into 2 diseases based on the mutational status of the expressed IG variable region sequences, unmutated (U) or mutated (M). U-CLL and M-CLL have a distinctive cellular origin, biology, epigenetics/genetics, and clinical behaviour. We investigate the hypothesis that the origin of U-CLL lies among the natural antibody-producing B cells, and that dominance of IGHV1-69 reveals a selective pressure by (super)antigenic structures located at tissue sites on initiation, maintenance and progression of this tumour. The balance between proliferation and anergy will define outcomes favouring proliferation and a more aggressive disease in U-CLL, or anergy and a less aggressive disease in M-CLL. Inhibition of BCR-associate signalling by small molecules (e.g. BTK inhibitors+/- BH3-mimetics) is very effective but escape mechanisms exist. 

Mechanisms that circumvent BTK inhibition or BCL2 inhibition, Richter transformation and immunosuppression remain challenges that we aim to study further in our group.

We also investigate the role of individual isotype in affecting the biology and clinical behaviour of CLL.

Hairy cell leukaemia (HCL)

We were the first to report mechanisms of multiple isotype expression and potential links between BCR IGHV gene structure/status and prognosis in the rare form of B-cell leukaemia HCL. With over 33 original publications in this very rare disease, we contributed to the first studies demonstrating the universal BRAF V600E mutation in HCL and to its diagnostic role. This has led to a number of clinical trials investigating efficacy of BRAF inhibitor vemurafenib and to co-authoring the revision of the international and UK guidelines for the diagnosis and treatment of this rare B-cell malignancy.

We have designed new investigator-led trials with the used of BTK inhibitors and BCL2 inhibitors in HCL.

Professor Francesco Forconi has been an executive member of the International Hairy Cell Leukaemia Consortium since it's foundation.

Mature Lymphoid Malignancies observational Study (MLMS)

This study is a longitudinal observational study that aims to investigate the phenotypic, functional, and molecular characteristics of patients with mature lymphoid malignancies in the UK.

We recruit patients with B-cell malignancies, focusing on chronic lymphocytic leukaemia (CLL). CLL is the most common type of leukaemia in adults. We are currently recruiting patients from the University Hospital Southampton NHS Foundation Trust Haematology clinic and five other centres in the UK (primarily in the Wessex region).

Patients provide samples of peripheral blood and/or surplus diagnostic tissue. Repeat samples are collected at clinical endpoints within the patient pathway, specifically disease progression and transformation. All samples undergo molecular profiling, including flow cytometry, signalling assays and IG sequencing within the laboratory. The samples are then stored in our biobank for further research use.

Recruited patients also undergo longitudinal follow-up, with clinical data being routinely collected on:

  • demographics
  • disease characteristics
  • treatment details
  • medical history
  • comorbidities
  • outcomes

We hope to gain insights into the biology, prognosis, and treatment response of mature lymphoid malignancies, and to identify novel biomarkers and therapeutic targets for future research. We have generated a comprehensive repository of clinical, molecular and research data alongside a substantial biobank of B-cell samples which has become a precious resource within our lab, and our collaborative network.