Affiliated Programme based at the University of Leicester

Programme Leader: Martin Dyer

Dyer Group

Summary of Research Interests

We are interested in the molecular pathogenesis and mechanism-based, targeted therapy of B-cell malignancies.

The former studies have been largely cytogenetically driven and have resulted in molecular cloning of many chromosomal translocations that play pivotal roles in the pathogenesis of disease. Genes identified using this approach include the BCL7 family, BCL9, BCL10 and BCL11 family. More recently, these studies have identified several new translocations in acute lymphoblastic leukaemia that not only define new prognostically important subgroups of disease but also new therapeutic targets.

In terms of therapy, we have been involved in the development and assessment of new targeted agents including antibody constructs and small molecules targeting BCL2 family members. One of the strengths of the group has been to translate in vitro findings directly into the clinic.

We have also established a unique population-based clinical and laboratory CLL database containing data from over 600 consecutive patients. Eighty new patients with CLL per annum are seen in the clinic in Leicester representing the incidence of CLL in a population of just over a million. All patients are entered into our database with comprehensive laboratory data detailing biological and prognostic features including IGHV mutational and interphase FISH data. This is an invaluable resource.

We collaborate widely with several other groups within the MRC Toxicology Unit, in the University of Leicester and with several groups world-wide, in particular with Professor Reiner Siebert’s group in Kiel.

Proteomic studies of the cell surface membrane of B-cell malignancies

(In collaboration with Drs Rob Boyd and Dr Kelvin Cain’s Group)

One major stream of research is aimed at identifying the physiological role of B cell specific protein that are potential therapeutic targets. In order to define proteins expressed at the cell surface of B-cell malignancies, and thus define new therapeutic targets, we have undertaken a proteomic survey of the cell surface membrane of CLL and more recently, Mantle Cell Lymphoma, MCL (in collaboration with Drs R.S. Boyd and Kelvin Cain, MRC Toxicology Unit). We are characterising the role of some of these targets in normal B cell development and activation upon stimulation of the B cell receptor (BCR) and their potential role in B cell signalling.

Our work on the voltage-gated proton channel HVCN1 has shed new light on the role of proton channels during B cell activation and antibody responses.

anti-HVCN1

Figure 1

Immunohistochemistry of a tonsil section stained with anti-HVCN1 antibody. GC indicates germinal centre and FM follicular mantle. HVCN1 is expressed in the mantle region but not in the GC.

BRC b-cells

Figure 2

Confocal microscopy image of a BCR stimulated B cells. The BCR, IgM (green), co-localise with HVCN1 (in red). Lamp1 is a marker for late-endosomes/lysosomes (in blue).

Recent studies in Chronic Lymphocytic Leukaemia

(Dr Aneela Majid in collaboration Dr Sal Macip, and with Professor Cohen’s group)

CLL is a major focus for our group. We work closely with Professor Cohen’s group characterizing the defects in apoptosis in CLL cells from peripheral blood and after culture on CD154 transfected cells. A recent finding has been the massive up-regulation of p53 protein following stimulation in CLL cells – how CLL cells proliferate in the presence of wild-type p53 and whether p53 contributes to the observed drug resistance of stimulated cells is not clear.

A major clinical focus is study of the rationally-designed BCL2 inhibitor ABT-737 as described in recent publications. Clinical studies using this compound in CLL alone and in combination with monoclonal antibodies are being undertaken in Leicester.