Leukaemia Research Group
To understand the mechanisms by which intracellular signalling pathways become corrupted in acute myeloid leukaemia (AML) cells leading to deregulated cell survival, proliferation and growth. By targeting leukaemic cell survival, proliferation and growth, we aim to develop new therapeutic approaches and treatments.
Research Focus and Tools
- Kinase and phosphatase signalling pathways in hemopoiesis and leukaemia
- The hemopoietic stem cell niche and the stromal microenvironment
- Transcriptional and post-translational pathways of malignant transformation
- Mouse preclinical models of leukaemia
- The regulation of cell survival and apoptosis
L-R Back Row: Ben Green, Mellissa Brown, Nick Cummings, Tse Chieh Teh
L-R Front Row: Andrew Wei, Julie McManus, Sewa Rijal, Nhu-Y Nguyen, Mark Guthridge
The human body produces 1,000,000,000,000 blood cells daily! This occurs largely in the bone marrow and is a massive undertaking that must be very tightly controlled. Growth factors and cytokines are key regulators of blood cell production through their ability to control a number of fundamental biological responses that include cell proliferation (cell division), cell differentiation (commitment to a more mature cell identity) and cell survival. Critically, deregulation or “short-circuits” in the intracellular signaling pathways that regulate each of these cellular responses represents a classical hallmark of cancer and can lead to over-production of blood cells and leukaemia. The overall research focus of the Leukaemia Research Laboratory lies in understanding the fundamental molecular mechanisms by which cell proliferation, differentiation and survival become deregulated in leukaemia in order to identify new therapeutic targets and treatments.
Projects and Opportunities
- Targetting “survival kinases” in leukemic stem and progenitor cells
- The role of PI3K in regulating normal and malignant hemopoiesis
- The stem cell niche and leukemia
For current project opportunity descriptions please visit our honours page
Guthridge MA, Powell JA, Barry EF, Stomski FC, McClure BJ, Ramshaw H, Felquer FA, Dottore M, Thomas DT, To B, Begley GC, Lopez AF. (2006) Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch. EMBO J 25: 479-89.
Lonic A, Barry EF, Quach C, Kobe B, Saunders N, Guthridge MA. Fibroblast growth factor receptor 2 phosphorylation on serine 779 couples to 14-3-3 and regulates cell survival and proliferation. Mol Cell. Biol. 2008 28:3372-85.
Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, Ramshaw H, Woodcock JM, Xu Y, Guthridge M, McKinstry WJ, Lopez AF, Parker MW. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell. 2008 134:496-507
Barry EF, Felquer FA, Powell JA, Biggs L, Stomski FC, Urbani A, Hoffmann P, Wilce MC, Grimbaldeston MA, Lopez AF, Guthridge MA. 14-3-3:SHC scaffolds integrate phoshoserine and phosphotyrosine signaling to regulate PI 3-kinase activation and cell survival. J Biol Chem. 2009, 284:12080-90.
Jin L, EM Lee, HS Ramshaw, SJ Busfield, AG Peoppl, L Wilkinson, MA Guthridge, D Thomas, EF Barry, A Boyd, DP Gearing, G Vairo, AF Lopez, JE Dick and RB Lock. Monoclonal antibody-mediated targeting of CD123 (IL-3 receptor a chain) eliminates human acute myeloid leukemic stem cells. Cell Stem Cell. 2009, 5:31-42.
Jason A. Powell, Daniel Thomas, Emma F. Barry, Chung H. Kok, Barbara J. McClure, Anna Tyskin, L. Bik To, Anna Brown, Ian D. Lewis, Gregory J. Goodall, Terence P. Speed, Norio Asou, Bindya Jacob, Motomi Osato, David Haylock, Susan Nilsson, Kirsten Herbert, Richard J. D'Andrea, Angel F. Lopez and Mark A. Guthridge. Expression profiling of a hemopoietic cell survival transcriptome implicates osteopontin as a functional prognostic factor in AML. Blood. 2009, 114:4859-70.
Van Delft M, Wei A, Chen L, Willis S, Adams J, Huang D. BH3 mimetic ABT-737 induces Bax/Bak-mediated apoptosis, but efficient killing requires Mcl-1 neutralization. Cancer Cell. 2006 Nov;10(5):389-99.
Chen L, Willis S, Wei A, Hinds M, Colman P, Adams J, Day C, Huang D. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Molecular Cell 2005;17:393 403
We receive funding from the National Health and Medical Research Council (NH&MRC), the Leukaemia Foundation of Australia (LFA), the Victorian Cancer Agency and the Alfred Foundation.