Haematopoietic stem cells and cancer stem cells in leukaemia
Unremitting production of blood during life is reliant on haematopoietic stem cells (HSCs).
A rare and relatively quiescent cell type harboured in adult bone marrow, HSCs are, on entry into cell cycle, fated to self-renew, undergo apoptosis or differentiate to progenitors (HPCs) that eventually yield specific classes of blood cells. Sustained perturbation of any of these cell fate decisions in HSCs or HPCs corrupts their functional integrity and is considered to be fundamental to the emergence of aplastic and dysplastic bone marrow failure syndromes and haematological malignancy.
We are identifying the transcriptional and post-transcriptional mechanisms regulating haematopoietic stem and progenitor cells and their dysregulation in the context of the pre-malignant blood disorder, myelodysplasia, and in acute myeloid leukaemia.
Current efforts are directed at investigating how these molecular mechanisms are disrupted in HSCs/HPCs to drive cancer stem cell formation in MDS and AML. MDS, as a pre-malignant disorder, is of particular interest as it provides a tractable model of the earliest stages of blood cancer stem cell development. The ultimate therapeutic aim, in addition to supplementing our understanding of how blood cancer stem cells sustain tumour growth, is to identify highly specific 'targetable' effector pathways in MDS and AML cancer stem cells, associated with transcriptional dysregulation in these diseases.