Cytokine signalling in myeloid leukaemia
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
Dr Anissa Jabbour (Primary) |
Cell Signalling and Cell Death | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Cell Signalling and Cell Death | .(JavaScript must be enabled to view this email address) |
Details of project
Constitutive activation of signalling kinases in leukaemia facilitates cell proliferation in the absence of growth factors or cytokine signalling. Interleukin-3 (IL-3) and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) normally regulate blood cell proliferation through a shared intracellular receptor. When IL-3 or GM-CSF is removed, dependent cells kill themselves by a mechanism that can be regulated by the Bcl-2 family of apoptosis regulators. The genes that regulate this process are likely to be important in the development of leukaemia since leukaemic cells acquire the ability to survive and proliferate independently of growth factors.
The projects in the laboratory seek to determine how growth factors promote cell survival, and how oncogenes regulate growth factor-independent proliferation. The projects will provide students with opportunities to master a wide range of cell biology and molecular biology techniques including PCR, cloning, tissue culture, flow cytometry, confocal microscopy, Western blotting and co-immunoprecipitation. In addition, students will learn about gene expression techniques and gene discovery, as they address the importance of various genes in the biology of tumours such as myeloid leukaemia.
Project references
- Jabbour AM, Daunt CP, Green BD, et al. Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. Blood. 2010 Jan 14;115(2):344-52. PMID: 19965665
- Jabbour AM, Heraud JE, Daunt CP, Kaufmann T, Sandow J, O'Reilly LA, Callus BA, Lopez A, Strasser A, Vaux DL, Ekert PG. Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim. Cell Death Differ. 2009 Apr;16(4):555-63. PMID: 19079139
- Ekert PG, Jabbour AM, Manoharan A, Heraud JE, Yu J, Pakusch M, Michalak EM, Kelly PN, Callus B, Kiefer T, Verhagen A, Silke J, Strasser A, Borner C, Vaux DL. Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma. Blood. 2006 Sep 1;108(5):1461-8. PMID: 16705087
Research interests
Our research focuses on how cytokines promote cell survival in blood cells, in particular myeloid cells. Myeloid cells transformed with the homeobox gene, HoxB8, depend on interleukin-3 (IL-3) for their continued proliferation. Withdrawal of IL-3 from these dependent cells initiates apoptosis.
IL-3 withdrawal-mediated apoptosis is regulated by the Bcl-2 family of proteins. Using these IL-3 dependent myeloid cells we are deciphering which signalling kinases are required for cell survival, which Bcl-2 family members are crucial for cell survival/cell death responses and which oncogenes can co-operate with IL-3 to promote leukaemiagenesis. The key kinases and oncogenes we are interested in are AKT, Jak2, HoxB8, HoxA9, p53 and WT1.
Selected publications
- Hercus TR, Thomas D, Guthridge MA, Ekert PG, King-Scott J, Parker MW, Lopez AF. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood. 2009 Aug 13;114(7):1289-98. PMID: 19436055
- Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59. PMID: 18097445
Research theme
Cancer
Scientific discipline
- Cell Biology
Keywords
Apoptosis, Acute Myeloid Leukaemia