Guthridge Group - Acute Myeloid Leukaemia

Group Leader
Dr Mark Guthridge

PhD Student
Ms Minhee Halemba

Goals

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

The group

Mark Guthridge group
2017. L-R: Ms Suelyn Van Den Helm, Dr Giovanni Monaco, Dr Mark Guthridge, Ms Minhee Halemba.

Research Overview

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

  1. Targetting “survival kinases” in leukemic stem and progenitor cells
  2. The role of PI3K in regulating normal and malignant hemopoiesis
  3. The stem cell niche and leukemia

For current project opportunity descriptions please visit our honours page

Selected Publications

Hein N, Cameron DP, Hannan KM, Nguyen NN, Fong CY, Sornkom J, Wall M, Pavy M, Cullinane C, Diesch J, Devlin JR, George AJ, Sanij E, Quin J, Poortinga G, Verbrugge I, Baker A, Drygin D, Harrison SJ, Rozario JD, Powell JA, Pitson SM, Zuber J, Johnstone RW, Dawson MA, Guthridge MA, Wei A, McArthur GA, Pearson RB, Hannan RD. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood. 2017, 129(21):2882-2895

Lalaoui, N., Hanggi, K., Brumatti, G., Chau, D., Nguyen, N.N., Vasilikos, L., Spilgies, L.M., Heckmann, D.A., Ma, C., Ghisi, M., Salmon, J.M., Matthews, G.M., Horat, E., Moujalled, D.M., Menon, M.B., Spall, S.K., Glaser, S.P., Richmond, J., Lock, R.B., Condon, S.M., Gugasyan, R., Gaestel, M., Guthridge, M.A., Johnstone, R.W., Munoz, L., Wei, A., Ekert, P.G., Vaux, D.L., Wong, W.W., Silke, J. Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell, 2016:29(2) 145-158.

Smith AM, Dun MD, Lee EM, Harrison C, Kahl R, Flanagan H, Panicker N, Mashkani B, Don AS, Morris J, Toop H, Lock RB, Powell JA, Thomas D, Guthridge MA, Moore A, Ashman LK, Skelding KA, Enjeti A, Verrills NM. Activation of protein phosphatase 2A in FLT3+ acute myeloid leukemia cells enhances the cytotoxicity of FLT3 tyrosine kinase inhibitors. Oncotarget. 2016,  7(30):47465-47478.

Lim, G., Albrecht, T., Piske, M., Sarai, K., Lee, J.T., Ramshaw, H.S., Sinha, S., Guthridge, M.A., Acker-Palmer, A., Lopez, A.F., Clee, S.M., Nislow, C., Johnson, J.D. 14-3-3{zeta} coordinates adipogenesis of visceral fat, Nature Communications, 2015:6(7671) 1-17.

Phillipson, L.J., Segal, D., Nero, T.L., Parker, M.W., Wan, S., de Silva, M., Guthridge, M.A., Wei, A., Burns, C.J. Discovery and SAR of novel pyrazolo[1,5-a]pyrimidines as inhibitors of CDK9, Bioorganic & Medicinal Chemistry, 2015:23(19) 6280-6296.

Rijal, S., Fleming, S.A., Cummings, N., Rynkiewicz, N.K., Ooms, L.M., Nguyen, N.N., Teh, T., Avery, S., McManus, J.F., Papenfuss, A.T., McLean, C.A., Guthridge, M.A., Mitchell, C.A., Wei, A. Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML, Blood, 2015:125(18) 2815-2824.

Current Grants

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.