Chronic myeloid leukaemia (CML) is a clonal disorder, initiated by the expression of the BCR-ABL1 oncogene in cancer stem cells. Most CML patients must take Tyrosine kinase inhibitors (TKIs), such as imatinib mesylate indefinitely, thus TKIs represent a life-long treatment without providing true cure. Our group and others have identified that in CML the existing residual disease, resistant to TKIs is comprised of leukaemic stem cells (LSC). To investigate the biology behind this critical tumour-initiating and maintaining subpopulation, we have conducted systems approaches providing deeper insight into CML and importantly, engineered a more fundamental synthetic lethality proving superior to single target approaches (Abraham et al. Nature. 2016 Jun 8;534(7607):341-6.). To complement and further this work, we are currently investigating extracellular factors and signalling events within the tumour milieu that promote malignancy and identifying biomarkers critical to early diagnosis.
2) Analyse extracellular vesicles (EVs) produced by stem cells over the lifetime of humans, in order to identify if EVs modulate HSC toward key decision-making processes such as self-renewal, differentiation, quiescence or death
Aging can be defined as a time-dependent physiological decline that slowly impairs tissue homeostasis and leads to a block of the regeneration capacity of organs. Nine candidate ‘aging hallmarks’ have been proposed in the literature, in attempts to define the cellular and molecular processes that specifically contribute to aging which include: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.
Interestingly, as both humans and mice age there is an increase in the number of HSC with a concurrent decrease in stem cell self-renewal capacity and reconstitution potential upon transplantation. Based on previous observations, it was also assumed that cell-intrinsic mechanisms predominantly drove the observed increase of aged HSC, however current studies show that HSC are additionally regulated by extrinsic factors outside the cell. We are investigating circulating EVs produced at different life stages of healthy humans to understand global signalling events that affect the maintenance of HSC during adult human development. Understanding the basic biology and functional characterization of circulating EVs will shed light into extracellular processes contributing to aging stem cells.