Understanding differences between childhood and adult AML
Relapse is the commonest cause of death in children with acute myeloid leukaemia (AML). The risk of relapse is high and has not improved significantly in the last twenty years. Relapse is due to the persistence of leukaemia stem cells that remain after treatment. We are interested in the biology of leukaemic stem cells in paediatric AML, and specifically how understanding the biology can help to improve treatment. The appropriateness of the current practice for some cancers to simply extrapolate treatments across the age spectrum is dependent on the assumption that the same aetiology underlies cancer in the young and old. However, significant age related biological differences are recognised in leukaemia aswell as in normal haemopoiesis. There are a number of projects in the lab investigating how the differences in the biology of leukaemia in the young and old, and the response to therapy, are impacted by stem cell age and its niche. Our research, together with industrial links investigates novel therapies and mechanisms of disease relapse in paediatric AML. We have a strong collaboration with Prof Brenda Gibson, clinical investigator for the international Paediatric AML trial MyeChild 01, which opened 2016. Our collaboration brings together our expertise in AML to improve our understanding of the fundamental aspects of AML biology with a clinical focus.
TRIB proteins are pseudokinases, and adaptor/scaffold proteins linking the proteasome pathway and MAPK signalling in leukaemia. We have shown TRIB proteins to have oncogenic and tumour suppressor properties in myeloid and lymphoid leukaemia, in both adult and paediatric leukaemias. The mechanisms that underlie whether TRIB proteins act as oncogenes or tumour suppressors are a focus of this lab. Oncogene or tumour suppressor activities may be determined by cellular context and linked to TRIB function on cell proliferation and in the cell cycle, protein degradation, transcriptional regulators (e.g. C/EBPalpha) or MAPK pathway modulation. We collaborate with pseudokinase & pseudoenzyme structural and cellular biologists worldwide and through a Tribbles network we are striving to provide expertise and advanced knowledge on these class of proteins. There are 518 (pseudo)kinases in the human kinome of which only a handful are studied, understood, or targeted for therapy. The pleiotropic role of TRIB proteins in leukaemia makes them important new pharmaceutical targets. There are a number of projects in the lab focused on the role of TRIB proteins in leukaemia and the development of novel small molecules for the therapeutic targeting of TRIB proteins in leukaemia.
Tribbles Biology & leukaemia
Specific projects in the lab on Tribbles proteins;
Understanding the regulation of the cell cycle by Tribbles proteins TRIB1, TRIB2 and TRIB3.
Identification of the cell context specific activities of TRIB2 using systems biology approaches.
Therapeutic targeting of Tribbles proteins in Leukaemia.
Specific projects on AML include:
Determination of the impact of cellular age on leukaemic transformation.
Genome editing of haemopoietic stem cells using CRISPR/CAS9 technology to investigate stem cell ageing and susceptibility to transformation.
Creating an in vitro niche for acute myeloid leukaemic stem cells.
Targeted therapy of leukaemic stem cells in childhood acute myeloid leukaemia