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Professor Jon Strefford

Professor Jon Strefford

 PhD
Head of School

Accepting applications from PhD students.

Connect with Jon

Email: jcs@soton.ac.uk

Address: Southampton General Hospital, Tremona Road Shirley, SO16 6YD (View in Google Maps)

Research

Research groups

Member of:

Current research

Research interests

Our research group is interested in the analysis of the genome and epigenome of mature B-cell tumours. Over three billion base-pairs of deoxyribonucleic acid (DNA), bound with accessory proteins in the form of chromatin, are super-coiled and packed into 23 autosomal and sex-determining chromosomes, constituting the human genome, the genetic blueprint for normal human development and cellular function.

A leukaemic cell, in addition to carrying this diploid genome that has been inherited from both parents, has also acquired a series of somatic genomic lesions, including base-pair mutations, chromosomal rearrangements and large-scale copy number alterations (CNAs). Epigenetic defects in the form of disordered DNA methylation, chromatin remodelling and dysregulation of small noncoding micro-ribonucleic acids (miRNAs) are also present.

The acquisition of these (epi)genomic defects can enable many of the hallmarks of leukaemogenesis, such as the promotion of proliferative signalling, the evasion of growth suppression and the resistance to apoptosis. Our work has involved the identification and characterisation of these defects, and these insights have helped us understand the leukaemic process, improving cancer diagnosis, accurate risk-adapted stratification and the development of targeted treatments for precision medicine.

Our laboratory works on a number of B-cell tumours, principally chronic lymphocytic leukaemia (CLL) and splenic marginal zone lymphoma (SMZL), and to a lesser extent follicular (FL) and diffuse large b-cell lymphoma (DLBCL). CLL is the most common form of leukaemia in Western populations, accounting for approximately one-third of all new diagnoses.  Clinically, the disease is highly heterogeneous, with patients surviving for decades with a benign disease requiring no treatment, while others exhibit a rapidly progressive disease despite aggressive therapy. SMZL is considered a low grade, indolent B-cell neoplasm with a median survival of approximately 10 years, but 70% of patients present with or develop progressive disease with a requirement for therapy, and 5–10% will undergo transformation to a large B-cell lymphoma. For both diseases, no biomarkers accurately predict the disease course, particularly in early stage disease. Furthermore, definitive diagnosis of SMZL can be challenging.

In CLL, we have identified, or help characterize many of the recurrently mutated genes emerging from recent high-throughput sequencing studies. We continue to be at the centre of large international collaborative studies, mapping the CLL genome and assessing the clinical importance of gene mutations. In SMZL, we published one of the seminal studies identifying KLF2 as a target of novel recurrent gene mutations. We currently lead a large international study investigating the importance of somatic mutations and DNA methylation changes in SMZL.

Previous PhD Supervision

Lara Buermann - 2022
Carolina Jaramillo – 2021
Rachel Dobson – 2018
Stuart Blakemore – 2018
Kate Packwood – 2017
Jade Forster – 2016
Victoria Hammond – 2010
Helen Parker – 2008
Lisa Russell - 2007

Research Projects

The Genomic landscape of mature B-cell tumours

One of our principle interests is in the characterization of the CLL and SMZL genome, identifying recurrent chromosomal deletions and somatic mutations that can aid in more appropriate clinical management. We employ sophisticated sequencing approaches and comprehensive computational analysis to unravel the genomic landscape of CLL and SMZL tumour cells. We collaborated with other international opinion leaders to elucidate the biological and clinical importance of these DNA mutations. One of our key on-going projects focused on the importance of genomic complexity in CLL, based on the observation that patients exhibiting a high number of genomic lesions in their cancer cells, exhibit poor survival. We now lead national and international studies aimed at defining exactly what level of complexity is most clinically relevant, and how this measure can most accurately aid patient management.

Molecular mechanisms contributing to the survival of B-cell neoplasms.

In collaboration with Professor Graham Packham and Dr Francesco Forconi

This project focuses on understanding the impact of signalling via the B-cell receptor (BCR) and the microenvironment on the epigenome of CLL cells, particularly the dysregulation of miRNAs and DNA methylation, as well as chromatin remodelling. In vitro analysis of signalling has previously demonstrated that individual CLL samples vary in their ability to transmit signals via the cell surface BCR. Retained signalling is associated with the presence of poor prognostic markers and a poor clinical outcome. Thus, antigen signalling via the BCR, in the context of specific tissue microenvironments, is considered to play a key role in driving cell proliferation and survival, leading to disease progression. We employ state-of-the-art next generation sequencing approaches to identify epigenomic determinants of differential B-cell receptor responsiveness in tumour cells. These observations will have clinical utility, such that they will predict the aggressiveness of the disease or identify the most appropriate treatment.

(Epi)genomic analysis of the Fc gamma receptors (FcgR) in normal and malignant B-cells

In collaboration with Dr Jane Gibson and Professor Mark Cragg

Fc gamma receptors (FcgRs) are a protein family expressed by a variety of immune cells. Current evidence indicates that almost all monoclonal antibody therapies act by engaging FcgR in the host. The low-affinity FcgRs are encoded by a 200Kb gene cluster at 1p24, that is highly repetitive and difficult to study with traditional technologies. This project focuses on the application of long-read sequencing technologies to generate detailed sequencing maps of the FCGR in normal and malignant immune cells.

Research projects

Active projects

Completed projects

Sponsor: F. Hoffmann-La Roche Ltd
Sponsor: Blood Cancer UK
Sponsor: F. Hoffmann-La Roche Ltd
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