Research Interest

Chronic Lymphoproliferative Disease

Chronic lymphoproliferative diseases are a group of diseases resulting from the malignant transformation of a variety of peripheral lymphoid cells. The commonest of these diseases, is chronic lymphocytic leukaemia (CLL), which is leukaemia of small mature lymphoid cells with a relatively indolent clinical course.  It presents with the features of anaemia, weight loss, lymph gland swelling and a large spleen.  There is often a raised white cell count, which can go to very high levels.  These circulating cells are characterised by the expression of CD5 on their surface and belong to the B cell lineage.  The biology and the molecular abnormalities of these cells, is of great interest, as they can predict clinical outcomes and we are developing targeted treatment strategies for each of these important biological subgroups.

Research in this area has largely followed the approaches and strategies used to study myeloma; outlined above.  In addition, we have paid particular attention to the classification of the various disease entities by the use of experimental tools to classify the disorders in terms of the molecular events, which distinguish the cancerous cells from their normal counterparts.

We have focused predominantly on CLL but have also studied other B and T-cell lymphoproliferative disorders investigating their cell biology, diagnosis and prognostic factors as well as the role of novel therapies.

Chronic lymphocytic leukaemia

We maintain a database containing more than 500 CLL patients with all the clinical and laboratory parameters. This database enables us to identify treatment resistant patients, which will be characterised further to define the molecular basis of treatment resistance in CLL. We are in the process of analysing the tumour characteristics of these patients in relation to transcription factors and cell survival pathways and plan to identify valid treatment targets with the aim of developing small molecular inhibitors in collaboration with phase 1 drug development unit.

We have a comprehensive frozen DNA and cell bank from the majority of patients entered into the UK CLL 4 clinical trial. Our results have shown that patients carrying a deletion of the chromosome 17p (p53) respond poorly to the standard treatments and should be treated in an alternate fashion. Furthermore patients withTP53 mutation respond poorly to treatment and also has a shorter overall survival. A further study using array CGH is exploring the structure and size of deletional and amplification events to define prognostic groups and targets for treatment.

In addition, there is a distinct subgroup of CD5 positive small cell leukaemia which does not full fill the CLL diagnostic criteria on immunophenotyping (“atypical CLL”). We are in the process of identifying new ways of classifying this group of patients based on immunophenotypic, molecular and clinical characteristics. Mutational status, gene segment usage, gene expression signatures, Bcl-3 translocations as well as NFkB DNA binding will be analysed in CD5+ positive malignancies such as ‘typical’ and ‘atypical’ CLL, MCL and CD5+SMZL.

B-cell prolymphocytic leukaemia (B-PLL)

This is a rare B-cell disease. Although recognized by the WHO, there is a debate as to whether it represents a distinct clinico-biological entity or instead is a variant form of CLL or a leukaemic mantle-cell lymphoma. Preliminary studies by our group show that B-PLL, like CLL, is heterogeneous in CD38/ZAP-70 expression and IgVH mutations. However, unlike in CLL, these factors do not appear to have a prognostic impact. Of interest is the restricted IgVH usage in B-PLL: prolymphocytes from all patients investigated, whether or not they have IgVH mutations, use the VH3 or VH4 segments. We have initiated microarray studies and our findings suggest that the pattern of gene expression in B-PLL is different from both CLL and CLL-with-increased-prolymphocytes (CLL/PL). This would indicate that B-PLL is a distinct B-cell condition.

B-cell disorders with circulating villous lymphocytes

This group of B-cell disorders encompasses three conditions: hairy cell leukaemia (HCL), hairy cell leukaemia variant (HCL-variant) and splenic marginal zone lymphoma with villous lymphocytes (SMZL/SLVL). The clinical outcome, response to therapy and probably their biology is significantly different. Data is scanty and controversial regarding the origin and differentiation status of the neoplastic cells in these conditions. It has been suggested, but yet to be proven, that there is a marginal zone origin of the hairy cell. We have started a study on these three disease entities analysing the IgVH mutations, the VH gene usage, gene expression profile and expression of certain antigens characteristic of the marginal zone aiming to establish whether there are similarities between these closely related disorders with regard to the cell origin and differentiation status and, if variability within a disease is found, its impact on response to treatment and survival

T-cell lymphoproliferative disorders

Our studies are focused on the two primarily T-cell leukaemias: T-prolymphocytic leukaemia (T-PLL) and T-cell large granular lymphocytic (T-cell LGL) leukaemia. Our group has pioneered the identification and description of the biological and clinical features of T-PLL as well as devising therapeutic strategies aimed to improve the dismal outcome in these patients. A study investigating the gene profile by microarrays and its correlation with other disease features is being carried out. Regarding T-cell LGL, we are investigating by flow cytometry the expression of a variety of molecules known to play a key functional role in cytotoxic and natural killer cells, such as NK-like receptors, and the different variable regions of the TCR beta chain. The aim is to better define the neoplastic lymphocyte and ascertain its prognostic relevance.

Nodal and extra-nodal indolent B cell lymphomas

We have been interested in cellular interactions that influence the growth and dissemination of indolent B cell lymphomas.  In particular we are involved in studies looking at the influence of infective organisms on the development of extra-nodal marginal zone lymphomas. In addition studies of variation in protein expression relating to the microenvironments of different areas of infiltration (follicular vs interfollicular; lymph node vs bone marrow) are being undertaken to try and identify cell-cell interactions that influence lymphoma growth and development and could potentially identify targets for future therapeutic strategies.

Team members
Saman Hewamana, Consultant Haematologist
Estella Matutes, Reader in Haematology
Claire Dearden, Consultant Haematologist
Daniel Catovsky, Emeritus Professor
David Gonzalez de Castro, Research Fellow
Monica Else, Higher Scientific Officer
Dr Andy Wotherspoon, Consultant Histopathologist
Dr Ayoma Attygalle, Consultant Histopathologist