The Johnstone Lab performs fundamental and pre-clinical research aimed at defining the molecular and biological processes underpinning the regulation of gene expression, tumorigenesis, anti-cancer drug activity and drug resistance.
Professor Ricky Johnstone is the Executive Director of Cancer Research at the Peter MacCallum Cancer Centre and Head, The Sir Peter MacCallum Department of Oncology at the University of Melbourne.
Major research themes in our laboratory include:
- Molecular characterisation of the RNA Polymerase II (POLII) transcription cycle and its regulation by cyclin-dependent kinases (CDKs);
- Investigating the role of epigenetic regulators that function aberrantly in cancer in order to develop novel therapeutic strategies: this includes the epigenetic regulation of the immune response;
- Dissecting the role of the immune system in tumorigenesis and response to anti-cancer therapeutics;
- Investigating the role of metabolic reprogramming in haematological malignancies and novel means to target the cancer metabolome;
- Development and use of multiple ‘omics’ approaches to discover novel therapeutic targets in haematological malignancies;
- Developing state-of-the-art mouse models that accurately recapitulate human disease.
Characterising and Targeting CDKS and the RNA Polymerase II (POLII) Transcription Cycle
CDK/Cyclin complexes regulate POLII and other transcriptional regulators at multiple checkpoints throughout the transcription cycle to control gene expression. The Johnstone lab investigates the coordinated functions of transcriptional CDKs in normal and cancer cells and the efficacy of targeting these enzymes for cancer therapy.
Targeting Epigenetic Regulators in Cancer
Cancer is a disease that is driven by progressive genetic abnormalities and epigenetic changes that can provide survival advantages that drive tumour onset and progression. Specific inhibition of enzymes that mediate these epigenetic defects can be exploited to induce anti-tumour activities. We focus on the development of novel agents that specifically target deregulated oncogenic proteins and pathways
The Immune System in Tumorigenesis and Anti-Cancer Drug Responses
Tumour cells interact with many different cell types, including immune cells, within their microenvironment. The immune system maintains a delicate balance between efficient killing of tumour cells and avoiding damage to healthy cells. Small molecule inhibitors can modulate:
i) The mechanisms through which tumour cells interact with immune cells and;
ii) The activity of immune cells against tumour and other immune cells
The Johnstone lab explores the use of novel agents and combination therapies to understand and to enhance the anti-tumour immune response.
Targeting Metabolic Vulnerabilities in Haematological Malignancies
Metabolic reprogramming is an emerging hallmark of cancer, and therapies that target the metabolome have been utilised for decades as the targets of chemotherapeutic agents, particularly in the context of haematological malignancies. The Johnstone lab is interested in investigating these reprogramming events and the subsequent metabolic vulnerabilities that emerge from these events, particularly in the context of acute myeloid leukaemia (AML).
Development of State-of-the-Art Mouse Models and Molecular Technologies
The Johnstone lab develops and employs pre-clinical small molecule inhibitors and novel enzyme inhibitory systems in combination with advanced next-generation-sequencing approaches, global phosphor-proteomics, genetically engineered mouse models of haematological and solid cancer and CRISPR-Cas9 whole-genome and targeted screens to dissect fundamental features of cancer cell biology and identify key drug sensitivity and resistance pathways.
Fan Z, Devlin JR, Hogg SJ, Doyle MA, Harrison PF, Todorovski I, Cluse LA, Knight DA, Sandow JJ, Gregory GP, Fox A, Beilharz TH, Kwiatkowski N, Scott NE, Vidakovic AT, Kelly GP, Svejstrup JQ, Geyer M, Gray NS, Vervoort SJ*, and Johnstone RW*. 'CDK13 cooperates with CDK12 to control global RNA polymerase II processivity', Science Advances. 2020. 6: eaaz5041. (In Press). (*Co-Senior Authors)
Kelly MJ, So J, Rogers AJ, Gregory GP, Li J, Zethoven M, Gearhart MD, Bardwell VJ, Johnstone RW, Vervoort SJ* and Kats LM*. 'Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis'. Nature Communications. 2019 Mar 22;10(1):1347. (*Co-Senior Authors)
Kim SK, Knight DA, Jones LR, Vervoort SJ, Ng AP, Seymour JF, Bradner JE, Waibel M, Kats L and Johnstone RW. 'JAK2 is dispensable for maintenance of JAK2-mutant B-cell acute lymphoblastic leukemias'. Genes and Development. 2018 Jun 1;32(11-12):849-864.
Kearney CJ, Vervoort SJ, Hogg SJ, Ramsbottom KM, Freeman AJ, Lalaoui N,, Pijpers L, Michie J, Brown KK, Knight DA, Sutton V, Beavis PA, Voskoboinik I, Darcy PK, Silke J, Trapani JA, Johnstone RW* and Oliaro J*. 'Tumour Immune evasion arises through loss of TNF sensitivity'. Science Immunology. 2018 May 18;3 (23). (*Co-Senior Authors)
Waibel M, Vervoort SJ, Kong IY, Heinzel, S, Ramsbottom, KM, Martin BP, Hawkins ED*, and Johnstone RW*. 'Epigenetic targeting of Notch1-driven transcription using the HDACi panobinostat is a potential therapy against T-cell acute lymphoblastic leukemia'. Leukemia. 2018 Jan 32 (1) 237-241. (*Co-Senior Authors)
Lefebure M, Tothill RW, Kruse E, Hawkins ED, Shortt J, Mathews GM, Gregory GP, Martin BP, Kelly MJ, Todorovski I, Doyle MA, Lupat R, Li J, Schroeder J, Wall M, Craig S, Poortinga G, Cameron D, Bywater M, Kats L, Gearhart MD, Bardwell VJ, Dickins RA, Hannan RD, Papenfuss AT, Johnstone RW. 'Genomic characterisation of Eµ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene'. Nature Communications. 2017 Mar 6;8:14581.
Hogg SJ, Vervoort SJ, Deswal S, Ott CJ, Li J, Cluse LA, Beavis PA, Darcy PK, Martin BP, Spencer A, Traunbauer AK, Sadovnik I, Bauer K, Valent P, Bradner JE, Zuber J, Shortt, J, Johnstone RW. 'BET-Bromodomain Inhibitors Engage The Host Immune System And Regulate Expression Of The Immune Checkpoint Ligand PD-L1'. Cell Reports. 2017 18 (9) 2162–2174.
Shortt J, Ott C, Johnstone RW*, Bradner JE*. 'A Chemical Probe Toolbox for Dissecting the Cancer Epigenome'. Nature Reviews Cancer. 2017-17(3) 160-183. (*Co-Senior and Corresponding Authors).
Ghisi M, Kats L, Masson F, Li J, Kratina T, Vidacs E, Gilan O, Doyle MA, Newbold A, Bolden JE, Fairfax KA, de Graaf CA, Firth M, Zuber J, Dickins RA, Corcoran LM, Dawson MA, Belz GT, Johnstone RW. 'Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia'. Cancer Cell. 2016. 30(1):59-74.
Please check back for new positions opening in our lab soon.