Billions of blood cells are produced in the body each day, due to the highly controlled regulation of self-renewal and differentiation processes of blood stem cells. Blood cell production predominantly occurs in the bone marrow and the non-blood cell types present in bone marrow (collectively called the bone marrow microenvironment) are important in helping to control blood cell production from all immature blood cell types. Incomplete production or function of the different blood cell types, or problems arising in the function or composition of the non-blood cells that regulate blood cell production, can lead to blood cell cancers such as myelodysplastic syndromes.
The Stem Cell Regulation Laboratory investigates how blood cell-forming stem cells are regulated to either increase in number (by a process termed ‘self-renewal’) or produce more blood cells (a process termed ‘differentiation’). This will lead to improved therapies for blood cell diseases, including the blood cell cancer, myelodysplastic syndromes. We also investigate how cells of the bone marrow microenvironment regulate blood cell production, and how this is altered in response to cancer therapies and in blood cell cancers, such as leukaemia.
We are passionate about translational research and collaborate with clinicians to deliver our research findings to patients.
Current research projects
The regulation of blood stem cell self-renewal and differentiation
Our research has pioneered the discovery that the different vitamin A receptors differentially regulate blood cell production. We have shown that vitamin A enhances blood stem cell self-renewal and that this requires one of the vitamin A receptors, retinoid acid receptor (RAR) gamma. We have also shown that the other receptor predominantly expressed by blood cells, RAR alpha, has the opposite effects on blood stem cells, enhancing their differentiation. Furthermore, we have developed two novel mouse models of the malignant blood cell disease, myelodysplastic syndromes (MDS), based on dysregulated expression of the RAR gamma target gene, HOXA1, and are currently using these models to determine how MDS occurs and find better therapies for this disease.The roles of the bone marrow microenvironment in regulating blood cell production
Mature blood cells are predominantly produced from blood stem cells located in the bone marrow microenvironment. The roles of the non-blood cell types that comprise the bone marrow microenvironment in regulating blood cell production are not well-defined. We have previously shown that the vitamin A receptor, RAR gamma, is a key regulator of haematopoiesis via bone marrow microenvironment cells. Our studies are further exploring how RAR gamma deletion in different bone marrow microenvironment cells alters blood cell production.Understanding how the cells of the bone marrow microenvironment respond to therapies used to treat cancers
Many drugs or irradiation procedures used to treat patients with a wide range of cancers cause severe and prolonged reductions in blood cell production, placing the patients at risk of bleeding or infection, which can be life-threatening. We have discovered that these cancer treatments not only affect the blood cells themselves, but also have major effects on the composition and function of the cells of the bone marrow microenvironment. We aim to improve recovery of the bone marrow microenvironment cells after cancer treatments, which in turn should aid in rapidly restoring blood cell production in these patients.Determining changes in bone marrow microenvironments in blood cell cancers
Blood cell cancers can cause changes in the bone marrow microenvironment, which, in turn, can alter normal haematopoiesis and facilitate the progression of the blood cell cancers. We are using advanced imaging technologies to determine these changes in human bone marrow biopsies in studies that form part of a clinical trial headed by our clinical collaborator, Dr Hang Quach.
- Kelli Schleibs, Research Assistant
- Lynette Mirembe, Research Assistant
- Wenxu Zhu, Masters student
- Winne Zhang, Honours student
Green AC*, Tjin G*, Lee SC, Chalk AM, Straszkowski L, Kwang D, Baker EK, Quach JM, Kimura T, Wu JY, Purton LE. The characterization of distinct populations of murine skeletal cells that have different roles in B lymphopoiesis. Blood 2021 138:304-317. DOI:10.1182/blood.2020005865 *Green and Tjin are co-first authors.
Duarte D, Hawkins ED, Akinduro O, Ang H, De Filippo K, Kong IY, Haltalli M, Ruivo N, Straszkowski L, Vervoort SJ, McLean C, Weber TS, Khorshed R, Pirillo C, Wei A, Ramasamy SK, Kusumbe AP, Duffy K, Adams RH, Purton LE, Carlin LM, Lo Celso C. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell 2018, 22:64-77. DOI: 10.1016/j.stem.2017.11.006
Hawkins ED, Duarte D, Akinduro O, Khorshed RA, Passaro D, Nowicka M, Straszkowski L, Scott MK, Rothery S, Ruivo N, Foster K, Waibel M, Johnstone RW, Harrison SJ, Westerman DA, Quach H, Gribben J, Robinson MD§, Purton LE§, Bonnet D§, Lo Celso C. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature 2016, 538:518-522. DOI 10.1038/nature19801 § Robinson, Purton and Bonnet are co-second last authors.
Joseph C, Nota C, Fletcher JL, Maluenda AC, Green AC, Purton LE. Retinoic acid receptor γ regulates B and T lymphopoiesis via nestin-expressing cells in the bone marrow and thymic microenvironments. The Journal of Immunology 2016, 196:2132-2144. DOI: 10.4049/jimmunol.1501246
Quach JM, Askymr M, Jovic T, Baker EK, Walsh NC, Harrison SJ, Neeson P, Ritchie D, Ebeling PR, Purton LE. Myelosuppressive therapies significantly increase pro-inflammatory cytokines and directly cause bone loss. JBMR 2015, 30:886-897. DOI:10.1002/jbmr.2415
Joseph C, Quach JM, Walkley CR, Lane SW, Lo Celso C, Purton LE. Deciphering hematopoietic stem cells in their niches: a critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell 2013; 13:520-533. DOI:10.1016/j.stem.2013.10.010
ORCID profile: 0000-0001-6593-3168
Google Scholar profile: https://scholar.google.com.au/citations?view_op=list_works&hl=en&user=RXmsf-kAAAAJ