Developmental Pathways Involved in Normal and Aberrant Haemopoietic Stem Cells
The stem cell group was established in 2009. Our group focuses on developmental pathways involved in normal and aberrant haemopoiesis, especially signals acting along conserved embryonic morphogenic pathways, including Wnt, Hedgehog (Hh), bone morphogenic protein (BMP), Notch pathways, and the Cdx-Hox transcription factors.
Haemopoiesis occurs within the architecture of the bone marrow (BM), a specialized microenvironment referred to as the stem cell niche where the hematopoietic stem cells (HSCs) reside and are regulated for quiescence, self-renewal and differentiation through intrinsic and extrinsic mechanisms. Leukaemia arises due to a genetic alteration in a HSC/progenitor cell giving rise to the presence of cancer stem cells (CSCs) that are predominantly quiescent, resistant to multiple therapies and capable of self-renewal. Eradicating these primitive CSCs which initiate and sustain the leukaemia is proving to be one of the toughest challenges faced by haematologists worldwide, as these cells are rare entities, reside within the protective BM microenvironment and display differential responses to growth factor stimuli compared to their non-malignant counterpart. Increasing evidence suggests that the embryonic morphogenic pathways are important for controlling self-renewal behaviour of HSCs and CSCs. Research suggests it may be possible to pursue eradication of CSCs by targeting these pathways. Especially since these pathways are deregulated in leukaemia and CSCs are more dependent on these following chemotherapy.
Our main focus is to determine the role these pathways play in CSC self-renewal and leukaemia disease progression. By identifying how CSCs survive we can evaluate the ability of combination treatments to eradicate the most primitive CSC populations responsible for minimal residual disease (MRD), relapse and disease progression. Our research uses a combination of primary patient samples and patient specific induced pluripotent stem cells (iPSC) as disease models. iPSC technology enables us to generate a renewable resource, of primitive stem cells for drug discovery. It is also enabling us to develop several models of the same leukaemia, but with different disease severity/stage or mutational status allowing us to evaluate the effects of individual drug regimes in progressive disease.