Treasurer
Sandra Irvine, PhD
Haematology Department,
Centre for Cancer Research and Cell Biology
Queen’s University Belfast
97, Lisburn Rd
Belfast BT9 7BL
Tel: +44(0) 28 90972794
Fax: +44(0) 28 9097 2776
Email: s.irvine@qub.ac.uk
Present Position:
Consultant Clinical Scientist/ Honorary Senior Lecturer,
Centre for Cancer Research and Cell Biology, Queen’s University Belfast.
Societies:
American Society for Haematology
European Haematology Association
British Society for Haematology
Association of Clinical Biochemists
Haematology Association of Ireland
Research Themes:
My research group is focused on studying the apoptotic mechanisms associated with the development of myeloid leukaemia. We have chosen to specifically concentrate on Chronic Myeloid Leukaemia which is characterised by the presence of the BCR-ABL onco-protein in more than 95% of patients. Through our collaborations with Professor Tony Whetton at University of Manchester and Professor Junia Melo at Imperial College London, we have access to unique cell line models for CML and in my role as a hospital clinical scientist I have access to patient samples to facilitate translational research. Initially we have used a model for chronic phase CML in which murine multi-potential haemopoietic stem cells (FDCP-Mix) have been transfected with a temperature sensitive BCR-ABL construct as a starting point to develop two main themes:
1) To identify candidate genes whose expression may be targeted by the BCR-ABL protein tyrosine kinase at an early stage in transformation.
2) To evaluate the potential of novel therapeutic strategies for the treatment of CML.
We performed microarray analysis to identify genes whose expression is altered as a consequence of 3 to 24 hours of expression of BCR-ABL kinase activity. Expression of CCN3 was downregulated by 15-fold as a consequence of BCR-ABL. CCN3 has previously been reported to function as a tumor suppressor gene in solid tumours; it has not previously been associated with hematologic malignancy. Northern and Western blotting plus immunocytochemical analysis confirmed CCN3 expression is decreased and is tyrosine phosphorylated in BCR-ABL kinase active cells. Decreased cellular CCN3 correlated with increased CCN3 expression in BCR-ABL kinase active cells. In vitro treatment of human CML cell lines with imatinib or siRNA directed against BCR-ABL significantly reduced BCR-ABL whilst increasing CCN3 expression. Cells from patients responding to imatinib showed a similar decrease in BCR-ABL and increase in CCN3. CML CD34+ cells tr
essor Bernard Perbal at the University of Paris. Perbal has prepared constructs in which each of the modules has been sequentially deleted. There have now been several reports of the existence of CCN3 isoforms, lacking 1 or 2 of the basic modules. For example an amino-truncated form of the molecule, missing the VWC and IGFBP modules has been detected in the nucleus of malignant cells. Transfection studies are currently underway with a human CML cell line model and it is also planned to produce recombinant CCN3 isoforms for further functional investigations. Preliminary experiments suggest that CCN3 has significant effects on haemopoietic stem cell function and may have therapeutic potential. Proteomics is being used to identify CCN3 binding partners in conjunction with the Proteomics Unit at Manchester University.
Recent Publications:
Mc Callum L., Price S., Planque N. , Perbal B. , Pierce A., Whetton A.D., Irvine A.E.
A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation.
Blood 2006; 108:1716-1723.
Crawford L.J.A. , Walker B. , Ovaa H. , Chauhan D. , Anderson K.C. , Morris T.C.M. , Irvine A.E. .
Comparative Selectivity and Specificity of the Proteasome Inhibitors BzLLLCOCHO, PS-341 and MG-132.
Cancer Res. 2006 ;66:6379-6386.
Hamza H.G., Pierce A., Stewart W.A., Downes P., Gray A.,Irvine A.E., Spooncer E., Whetton A.D..
Chronic Myeloid Leukemia CD34+ cells have elevated levels of phosphatidyl 3,4,5 triphosphate (PtdIns(3,4,5)P3 ) and lack a PtdIns(3,4,5)P3 response to cytokines and chemotactic factors: effects reversed by Imatinib.
Leukemia 2005; 19: 1851-1853.
Graham C. , Irvine A.E. , McClean S , Richter S , Flatt P.R., Shaw C
Peptide Tyrosine Arginine, a potent immunomodulatory peptide isolated and structurally chatacterized from the skin secretions of the dusky gopher frog, Rana sevosa.
Peptides2005; 26: 737- 743
Magill L. , Lynas J. , Morris T.C.M , Walker B. , IrvineA.E.
Proteasome proteolytic activity in haematopoietic cells from patients with chronic myeloid leukaemia and multiple myeloma.
Hematologica2004; 89: 1428-1433.
Bell A.L., Irvine A.E., Magill K., McKane R.
Fate of inflammatory neutrophils within the joint.
Rheumatology 2003; 42: 1274-1275.
Magill L. , Walker B. , Irvine A.E. .
The proteasome: a novel therapeutic target in haemopoietic malignancy
Hematology2003 ;8:275-284.
Morris T.C.M. , Magill M.K. , Ranaghan L. , Irvine A.E.
Prognostic Value of C-Reactive Protein and Cytokine Assays for Transplant Related Mortality.
Bone Marrow Transplantation 2004; 33: 121-122.
Ong Y.L., Irvine A.E .
Quantitative real-time PCR: A critique of method and practical considerations.
Hematology 2002: 7: 59-61.
Irvine A.E. , McMullin M.F. , Ong Y.L. .
Bcl-2 Family Members as Prognostic Indicators in AML.
Hematology 2002: 8: 21-31.
Morris T.C.M. , Magill M.K. , Drake M. , Price S. , Ranaghan L. , Bridgett S. , Jordan A. , Irvine A.E. .
The endogenous granulocyte colony-stimulating factor response following autologous peripheral blood stem cell transplantation is impaired in patients with myeloma.
Br J Haematol 2002; 117: 646-649.
Salmon A.L. , Cross L.J. , Irvine A.E., Lappin T.R.J., Dathe M. , Krause G. , Canning P. , Thim L. , Beyermann M. , Rothermund S. , Bienert M. , Shaw C..
Peptide leucine arginine, a potent immunomodulatory peptide isolated and structurally characterized from the skin of the Northern Leopard frog, Rana pipens.
J Biol Chem 2001; 276: 10145-10152.
Ong Y.L. , Jones F.G.C. , McMullin M.F., Lappin T.R.J , Irvine A.E. .
High bax expression is a good prognostic indicator in acute myeloid leukaemia.
Br J Haematol 2000; 111:182-189.