NHMRC Research Fellowship: How does the bone marrow regulate normal blood formation and leukaemia progression. (2013–2017)

This project is to determine how specific cues from the stem cell niche regulate the behaviour of normal haematopoietic stem cells (HSC) and leukaemia stem cells. Background: HSC replenish blood and immune systems and are the only stem cells routinely transplanted. Maintaining appropriate numbers of HSC and their progeny leukocytes is tightly regulated in the bone marrow (BM). Breakdown in HSC regulation leads to BM failure or malignancies. To better treat these conditions, it is critical to understand HSC regulation. Factors that control HSC decisions are their exact location in the BM (niches), the composition of these niches and key transcription regulators. Project: I hypothesise that a) haematopoiesis in the BM is functionally coupled with bone formation with innate immune cells and nerve cells regulating this coupling, b) niche components (proteins and physicochemical cues) critically regulate the fate of normal HSC as well as leukaemia cells (leukaemia progression and resistance to treatment) and c) manipulation of the pathways activated by these niche factors offers a therapeutic opportunity to improve the therapeutic use of normal HSC and further sensitise leukaemia cells to cytotoxic treatments. My specific aims are to 1) elucidate the role of the hypoxia sensing pathway in normal haematopoiesis and acute leukaemia, 2) elucidate how BM macrophages regulate niches for normal HSC and leukaemia stem cells (LSC) and bone formation, and 3) identify new endosteal niche factors that critically regulate haematopoiesis and bone formation. It is increasingly clear that niche factors play an unappreciated role in the progression of leukaemia. My research on novel niche factors will further expand the repertoire of targets to improve HSC based therapies (HSC mobilisation and ex-vivo expansion for transplantation) and develop new therapies that disturb interactions between leukaemia cells and niches promoting their development.
Grant type:
NHMRC Research Fellowship
Funded by:
National Health and Medical Research Council