MYELOPOIESIS RESEARCH GROUP

Dr Sandra Irvine

The Myelopoiesis Research Group is focused on studying the role of dysregulated apoptotic pathways in myeloid leukaemia.  Chronic Myeloid Leukaemia (CML) is characterised by the presence of the bcr-abl fusion gene which encodes a constitutively active tyrosine kinase.  This gene has been shown to make cells resistant to induction of apoptosis and thus contributes to the expansion of the leukaemic clone.  The group have used a murine cell line model for CML developed by collaborators at UMIST.  A temperature sensitive bcr-abl construct has been inserted in multipotent haemopoietic progenitor cells; when cells are grown at the permissive temperature the bcr-abl gene is active and the cells mimic CML, at the restrictive temperature the cells are normal. The researchers are characterising a novel gene called CCN3 which is an important regulator of calcium dependent signalling pathways and has not previously been associated with CML. They have shown that CCN3 expression is reduced in CML patients at diagnosis and returns to normal in response to treatment. This work is being carried out in collaboration with the universities of Manchester and Paris.

 A further group of genes associated with ubiquitination and proteasome function are being studied in collaboration with Professor Brian Walker, Department of Pharmacy.  The proteasome is a proteolytic complex found in all eukaryotic cells which plays a key role in regulating the proteins associated with the cell cycle and apoptosis. Assays for the component proteolytic activities of the proteasome have already been developed by the researchers and novel inhibitors of these activities demonstrate potent induction of apoptosis in vitro. They have found distinct enzyme profiles associated with drug resistant cells and are developing single cell assays to facilitate clinical investigations. Collaborative studies are currently underway with groups at Imperial College, London, Glasgow University and the Dana Faber Institute in Boston to examine the effects of these compounds on cells which have become resistant to conventional drug therapies to determine the underlying mechanisms involved.

1.      H.G.Hamza, A.Pierce, W.A.Stewart, P.Downes, A.Gray, A.E.Irvine, E.Spooncer, A.D.Whetton. 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.

 2.      L. Magill, J. Lynas, T.C.M Morris, B. Walker, A.E. Irvine Proteasome proteolytic activity in haematopoietic cells from patients with chronic myeloid leukaemia and multiple myeloma. Hematologica 2004; 89: 1428-1433.

3.      L. Magill, B. Walker, A.E. Irvine. The proteasome: a novel therapeutic target in haemopoietic malignacy Hematology 2003 ;8:275-284.

Figure 1:

Chronic Myeloid Leukaemia is characterised by the presence of the Bcr-Abl tyrosine kinase.  This constitutively active tyrosine acts on several key signalling pathways resulting in malignant transformation.

 

Figure 2:

In the murine cell line model of CML the Bcr-Abl kinase is active at 32oC.  When the kinase is active the expression of CCN3 is reduced.