Director, Northern Institute for Cancer Research
American Society of Hematology,
American Association for Cancer Research,
British Society of Haematology,
British Association of Cancer Research.
Using intensive combination chemotherapy more than 80% of children with acute lymphoblastic leukaemia (ALL) achieve long-term remission. However, relapsed ALL remains the most frequent cause of death from malignancy under the age of 15. My main research focus has been the study of the biology of relapse in ALL with the aim of discovering the causes of chemoresistance and suggesting ways of improving long-term survival in relapsed disease.
Previous studies undertaken by the Molecular Pharmacology Group in Newcastle have indicated that cell line models are of limited value in predicting mechanisms of drug resistance in patients. Our research has shown this may be in part be due to the fact that the majority of lymphoid cell lines are mismatch repair defective but that this is uncommon in the clinical setting (Matheson et al, 2003). We have shown, for example, that point mutations in the glucocorticoid receptor are a common cause of steroid resistance in CCRF-CEM cells, a frequently used, mismatch repair defective, T-cell line, but do not underlie resistance in mismatch repair proficient preB697 cells (Schmidt/Irving et al, 2006) and are very uncommon in clinical samples (Irving et al 2005).
These findings have led us to alter our approach to the study of drug resistance in leukaemia to focus on the use of clinical material. We have pioneered the use of single nucleotide polymorphism microarrays to determine allelic imbalance in leukaemic cells and have demonstrated progressive loss of heterozygosity in matched samples taken at presentation and on relapse (Irving et al, 2005). Studies are underway to extend these observations in collaboration with colleagues both in the UK and abroad and to develop ways of exploiting progressive change which we have identified.
A study of the prognostic significance of topoisomerase IIα in childhood acute lymphoblastic Leukaemia. In: 177th Meeting of The Pathological Society of Great Britain and Ireland. 1998, University of Leicester, Leicestershire, UK: Journal of Pathology: John Wiley & Sons Ltd.