The Leukaemia Stem Cell Self-Renewal group was established in 2008. Our research group is interested in the abnormalities of stem cell self-renewal and bone marrow microenvironment which develop in myeloid leukaemias. We have specific interests in the Hedgehog pathway in myeloid leukaemias, quiescence as a mechanism of drug resistance in leukaemia stem cells and interactions between leukaemia stem cells and their niche, in particular via the CXCL12/CXCR4 axis. An important aim of our work is the translation of basic laboratory research to clinical trials which we have achieved with the use of Hedgehog pathway inhibitors in chronic myeloid leukaemia.
Research interests
Aberrant leukaemia stem cell self-renewal and altered bone marrow microenvironment or “niche” allows the leukaemia stem cells to survive the most effective chemotherapeutic strategies available today, resulting in refractory leukaemia or relapse. Small molecule inhibitors are increasingly becoming available to target these essential stem cell pathways and assessing these novel compounds forms a very important part of our research.
We use a combination of immunomagentic cell separation and multi-parameter fluorescence activated cell sorting (FACS) to isolate the most primitive haemopoietic stem cells from the progenitor cells in both normal and leukaemic primary samples. We then use a combination of long and short-term culture techniques, together with a number of gene expression (microarray, Taqman qRT-PCR, Fluidigm) and protein expression/activity (Western blotting, flow cytometry, immunofluorescence) approaches to assess the differences between normal and leukaemic cells and the effects of small molecule inhibitors. In addition, we are currently involved with extending the leukaemia Biobank to include samples from patients with acute leukaemia and myelodysplastic syndrome.
We work with several academic collaborators including Professor Jon Cooper (Glasgow), Professor Peter Adams (Glasgow), Dr David Vetrie (Glasgow), Dr Kathryn Ball (Edinburgh), Professor Junia Melo (Adelaide) and Dr Ravi Bhatia (Duarte). We currently have industrial collaborations with Novartis, Genzyme and Bristol-Myers Squibb.
Individual projects:
• An investigation of the control of cell division and quiescence in leukaemic versus normal haemopoietic stem and progenitor cell
• Phase 1 clinical trial “Dasatinib (BMS-354825) combined with SMO inhibitor (BMS-833923; XL139) in CML either resistant to imatinib or nilotinib or with suboptimal response to any prior TKI
• Development of a biomarker assay for the assessment of Hedgehog pathway activity in hematological malignancies
• Hedgehog signalling as a leukaemia stem cell self-renewal pathway in CML.
• Antagonising the CXCR4/SDF-1 interaction in chronic myeloid leukaemia for sensitisation to tyrosine kinase inhibitors