Transformations that cause leukaemia allow cells to escape controls on unrestricted cell proliferation, in part by an increased resistance to cell death. This not only contributes to the transformation process but also to resistance to treatment. Our aim is to understand how cell death and survival signals are regulated in normal blood progenitor cells and the molecular mechanisms and consequences of their deregulation in leukaemic cells.
Aug 2015: L-R Ms Karla Fischer, Ms Carmel Daunt, Dr Anissa Jabbour
Our Laboratory is interested in how cytokines signal cell survival and proliferation, and how these pathways are deregulated in Acute Myeloid Leukaemia. Our group aims to understand how key kinase pathways, activated by the cytokines Interleukin (IL)-3 and GM-CSF, maintain healthy proliferation of myeloid progenitor cells and how deregulation of these kinases affects growth of leukaemia cells.
Our goals are to:
- Determine the role of key IL-3/GM-CSF activated kinases, in particular JAK2, AKT and IkappaB kinase (IKK)
- Identify how JAK2, AKT and IKK regulate cell survival signals
- Determine how activation of IL-3/GM-CSF receptors leads to regulation of the transcription factor and tumour suppressor p53
- Use genetic and pharmacological approaches to establish the efficacy of inhibiting specific kinases to treat chemotherapy resistant leukaemia
Bandopadhayay, P., Jabbour, A., Riffkin, C.D., Salmanidis, M., Gordon, L., Popovski, D., Rigby, L., Ashley, D.M., Watkins, D.N., Thomas, D.M., Algar, E.M., Ekert, P.G., 2013, The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts, BMC Cancer [P], vol 13, BioMed Central Ltd, London UK, pp. 1-14.
Brumatti, G., Salmanidis, M., Kok, C.H., Bilardi, R.A., Sandow, J.J., Silke, N., Mason, K.D., Visser, J.A.L., Jabbour, A., Glaser, S.P., Okamoto, T., Bouillet, P., D'Andrea, R.J., Ekert, P.G., 2013, HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia, OncoTarget [E}, vol 4, issue 11, Impact Journals LLC, Albany USA, pp. 1933-1947.
Salmanidis, M., Brumatti, G., Narayan, N., Green, B.D., van den Bergen, J.A., Sandow, J.J., Bert, A.G., Silke, N., Sladic, R., Puthalakath, H., Rohrbeck, L., Okamoto, T., Bouillet, P., Herold, M.J., Goodall, G.J., Jabbour, A., Ekert, P.G., 2013, Hoxb8 regulates expression of microRNAs to control cell death and differentiation, Cell Death and Differentiation [P], vol 20, issue 10, Nature Publishing Group, London UK, pp. 1370-1380.
Thomas D., Powell J.A., et al. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription. Blood. 122(5):738-48 (2013).
Green B.D.,* Jabbour A.M.,* et al. Akt1 is the principal Akt isoform regulating apoptosis in limiting cytokine concentrations. Cell Death Differ. 20(10):1341-9 (2013) (*equal contribution).
Sandow JJ, Jabbour AM et al. Cytokine receptor signaling activates an IKK-dependent phosphorylation of PUMA to prevent cell death. Cell Death Differ. 19:633-641, 2012.
Jabbour, A., Gordon, L., Daunt, C.P., Green, B.D., Kok, C.H., D'Andrea, R.J., Ekert, P.G., 2012, p53-dependent transcriptional responses to interleukin-3 signaling, PLoS ONE [E], vol 7, issue 2, Public Library of Service, San Francisco USA, pp. 1-11.
Jabbour, A., Daunt, C.P., Green, B.D., Vogel, S., Gordon, L., Lee, R.S., Silke, N., Pearson, R.B., Vandenberg, C.J., Kelly, P., Nutt, S.L., Strasser, A., Borner, C., Ekert, P.G., 2010, Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation, Blood [P], vol 115, issue 2, American Society of Hematology, Washington USA, pp. 344-352.