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Stem cell regulation

Billions of blood cells are produced in our body each day, due to 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 the bone marrow (collectively called the bone marrow microenvironment) are important in helping to control blood cell production from stem cells. 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 diseases such as cancers.

Research Overview

The Stem Cell Regulation Unit is interested in learning how stem cells, in particular blood cell-forming stem cells and bone-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). We are also interested in learning how cells of the bone marrow microenvironment (where blood stem cells normally reside) interact with blood stem cells to regulate both self-renewal of blood stem cells and blood cell production from blood stem cells. In a separate theme, we have also recently established the most faithful small animal model of osteosarcoma, a bone cancer that occurs predominantly in teenagers, and are using this model to determine processes involved in the initiation, progression and metastasis of this cancer.

Research Themes

Understanding RNA regulation in blood cell development and haematopoietic cancer

We are interested in how RNA is regulated and the role of this regulating in blood system and cancer development. We are interested in a process termed RNA editing – the direct coversion of adenoisine to inosine in RNA. This process is mediated by ADAR proteins. We are trying to understand how RNA editing by ADAR1 in particular contributes to blood system homeostasis and whether this plays a role in leukaemia development or progression.

The regulation of blood stem cell self-renewal and differentiation

We are investigating how stem cells are influenced by two different regulatory pathways as follows:

The vitamin A receptor pathway

Our research has pioneered the different effects of the vitamin A receptors in 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, based on altered RNA splicing of the RARgamma target gene, Hoxa1, we have developed two novel mouse models of the malignant blood cell disease, myelodysplastic syndromes, and are currently using these models to determine how MDS occurs and find better therapies for this disease.

Influences of cell cycle regulators on blood cell production

We are interested in understanding how the process of cell division is coupled to the fate of blood stem cells. For a stem cell to self-renew or to differentiate requires them to undergo division. Our recent studies have focused on understanding the roles of negative cell cycle regulatory genes (such as the retinoblastoma protein, pRb) in regulating blood stem cell fate. We are now exploring roles for the cell division cycle in other aspects of blood cell diseases, such as anaemia.

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 are determining how cells of the bone marrow microenvironment regulate blood cell production in both normal and diseased states.

Two major projects currently in force in our labs are as follows:

Determining the contribution of the bone marrow microenvironment to blood cell diseases.

Myeloproliferative diseases (MPDs) are blood cell diseases that are life-threatening and can progress to leukaemia. Patients who develop MPDs largely cannot be cured, mainly because there is very little understanding of how MPDs occur. MPDs are generally considered to arise from defects occurring in the blood cells. We have recently described two unique models of myeloproliferative-like diseases in which the MPDs are caused by cells of the bone marrow microenvironment. We are further exploring how the bone marrow microenvironment influences MPD development, and will determine if the bone marrow microenvironment can also contribute to the development of other blood cell cancers.

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.

Modeling osteosarcoma (bone cancer)

Osteosarcoma is the most common tumour of bone. We have developed and characterized a unique model of this tumour based on our understanding of the human disease. This model closely mirrors the human disease in terms of histology, transcriptional profile, cytogenetics and metastatic dissemination. We are using this faithful model of human osteosarcoma to further understand the genetics of this disease as well as a pre-clinical model to explore new therapeutic approaches to treat both primary and metastatic disease.

Honours and PhD Projects

Staff

  • A/Prof Louise Purton
  • A/Prof Carl Walkley
  • Dr Monique Smeets
  • Dr Alistair Chalk
  • Dr Mannu Walia
  • Ankita Gupte
  • Scott Taylor
  • Dr Shuh Ying Tan
  • Lenny Straszkowski
  • Dr Jacki Heraud-Farlow
  • Dr Gavin Tjin
  • Jane Xu
  • Blessing Crimeen-Irwin
  • Dr Wilson Castillo

Publication Highlights

  1. Walkley CR, JM Shea, NA Sims, LE Purton & SH Orkin. Rb Regulates Interactions Between Hematopoietic Stem Cells and their Bone Marrow Microenvironment. Cell 2007; 129: 1081-1095.
  2. Walkley CR*, G. Haines Olsen*, S Dworkin, SA Fabb, J Swann, GA McArthur, SV Westmoreland, P Chambon, DT Scadden & LE Purton. A Microenvironment-Induced Myeloproliferative Syndrome Caused by Retinoic Acid Receptor γ Deficiency. Cell 2007; 129: 1097-1110.
  3. Wu JY*, Purton LE*, Rodda S, Chen M, Weinstein LS, McMahon AP, Scadden DT, Kronenberg HM. Osteoblastic regulation of B lymphopoiesis is mediated by Gsalpha-dependent signaling pathways. PNAS 2008; 105:16976-16981.
  4. Chee LC, Hendy J, Purton LE, McArthur GA. ATRA and the specific RARa agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells. Leukemia 2013 27:1369-1380.
  5. 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 Nov 7;13(5):520-33.
  6. Smeets MF, DeLuca E, Wall M, Quach JM, Chalk AM, Deans AJ, Heierhorst J, Purton LE, Izon DJ, Walkley CR. The Rothmund-Thomson Syndrome helicase Recql4 is essential for hematopoiesis. J Clin Invest 2014 124:3551-3565.
  7. Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB*, Seeburg PH*, Walkley CR*. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as non-self. Science 2015 Sep 4;349(6252):1115-20.
  8. Ng AJ, Walia MK, Smeets MF, Mutsaers AJ, Sims NA, Purton LE, Walsh NC, Martin TJ, Walkley CR. The DNA Helicase Recql4 Is Required for Normal Osteoblast Expansion and Osteosarcoma Formation. PLoS Genet. 2015 Apr 10;11(4):e1005160
  9. 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. J Immunology 2016 196:2132-2144.
  10. 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 538:518-522, 2016.