The Keeshan Lab is a paediatric leukaemia research group with expertise in leukaemic stem cells, mouse models of myeloid and lymphoid leukaemia (AML & ALL), mechanisms of disease and response to novel therapeutics. We are based in the Paul O’Gorman Leukaemia Research Centre (POGLRC) which works closely with the University of Glasgow, Wolfson Wohl Cancer Research Centre (WWCRC) and the CR-UK Beatson Institute for Cancer Research (BICR), bringing together collaborative basic and clinical cancer research.

Our lab is interested in understanding the biology of normal and leukaemic stem cells during ontogeny, and identifying novel therapeutic targets. The lab uses state of the art retroviral and lentiviral (including CRISPR vectors) transduction and transplantation murine (syngeneic) and human (NSG) in vivo models. The murine models are optimised for stem cell ontogeny and niche interactions (fetal liver through to aged adult), and incorporate a number of AML and ALL models (e.g. TRIB2, MLL-AF9, AML1-ETO, HOX, NOTCH1). In vitro 2D and 3D models using novel surface chemistries are also used and being developed that mimic the stem cell niche for preclinical target validation in primary paediatric and adult AML cells.

Research Themes

Paediatric AML: 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.

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. In collaboration with Prof Brenda Gibson, Chief Investigator for the international Paediatric AML trial MyeChild 01, opened 2016, we are investigating novel therapies and mechanisms of disease relapse in paediatric AML.

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Tribbles Biology: 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. The mechanisms that underlie whether TRIB proteins act as oncogenes or tumour suppressors are a focus of this lab. The mechanism may be linked to TRIB function in cell proliferation, protein degradation, transcriptional regulators (e.g. C/EBPa) and MAPK pathway modulation. There are a number of projects in the lab focused on mechanisms of TRIB leukaemia and developing novel small molecules for the therapeutic targeting of TRIB proteins.

web portal Tribbles-Net

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