Professor of Leukaemia Stem Cell Biology
Research themes:Stem Cell, Cancer
Description of research
The aims of our group are broadly to study mechanisms of leukaemogenesis and leukaemia stem cell biology. In particular we aim to characterise leukaemia stem cells (LSC) at the molecular and cellular level in myeloid haematological malignancies. Leukaemias and many other cancers have recently been demonstrated to be wholly dependent upon a population of so-called cancer stem cells for their continued growth and propagation. These cells represent the most critical targets for treatment of leukaemia and a greater understanding of their biology and its interface with normal haematopoietic stem cell (HSC) function is fundamental to improving treatment outcomes.
We utilise a combination of functional and genomic assays in complementary mouse models and human primary cells to study normal HSC biology and how this is subverted in LSC and leukaemogenesis. An evolving paradigm in myeloid malignancies is transcriptional dysregulation and many of the mutations occurring in myeloid leukaemogenesis involve transcriptional and epigenetic regulators. Ongoing projects within the group look at aberrant transcription and epigenetic regulation, particularly in acute myeloid leukaemia (AML). We are looking at functions of epigenetic regulators and transcription factors such as CBP and SOX4 in HSC and LSC, and are generating murine models with mutations/knock out of epigenetic regulators known to be abnormal in AML. In addition we are looking at mechanisms of action of epigenetic therapeutic agents such as the bromodomain and extra terminal (BET) proteins in AML and are performing pre-clinical assays with these agents. In addition, we are interested in the evolution of myeloid preleukaemic disorders such as chronic myeloid leukaemia (CML) to acute leukaemia and generating mouse models and studies in human cells to outline disease mechanisms and identify therapeutic targets.
Our long-term aim is to improve biological understanding of leukaemogenesis, to identify rational targets and to design novel therapeutics to improve the outcomes in myeloid malignancies.
Keywords: Leukaemogenesis, leukaemia stem cell, haematopoietic stem cell, epigenetic regulators, translation factors, CBP, SOX4, BET
Clinical conditions: Leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia
Methodologies: Functional assays, genomic assays, complementary mouse models, human primary cells