Key terms: Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Tumour suppressor genes, Transcription factors, Differentiation therapy
2016. L-R: Mr Steven Ngo, Ms Emilia Simankowicz, A/Prof Ross Dickins, Dr Margherita Ghisi, Mr Ethan Oxley
Cancer results from an accumulation of genetic mutations that disable normal regulation of cell growth and survival. Genome sequencing of thousands of cancers has identified hundreds of recurrently mutated driver genes, comprising similar numbers of oncogenes and tumor suppressor genes. In acute myeloid leukemia (AML) ~100 driver genes have been identified, however an individual AML genome averages only 5 driver mutations. A key challenge towards developing more effective cancer therapies is understanding how individual driver gene mutations contribute to leukemogenesis and treatment response.
Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are characterised by failure of transformed blasts to undergo normal lineage maturation. Our laboratory is interested in understanding how driver mutations in acute leukemia contribute to this differentiation block, focusing on hematopoietic transcription factors including PU.1, CEBPA, PAX5, and IKAROS. We use reversible RNA interference (RNAi) and other genetic technologies to generate mouse leukemias that accurately recapitulate human leukemia genetics, and assess the functional consequences of oncogene withdrawal and/or tumor suppressor restoration in established leukemias in vivo. Using these tools we are gaining fresh insights into how loss of particular transcription factors contributes to leukemia cell self-renewal and therapy resistance. We also use these mouse leukemia models to identify genes critical for leukemia maintenance, which represent potential novel drug targets.
Our laboratory is funded by the National Health and Medical Research Council (NHMRC), and has previously been supported by the Leukaemia Foundation of Australia, the Sylvia and Charles Viertel Charitable Foundation, and VESKI.
- See more of Ross's publications on his Monash University Staff Profile
Witkowski MT, Hu Y, Roberts KG, Boer JM, McKenzie MD, Liu GJ, Le Grice OD, Tremblay CS, Ghisi M, Willson TA, Horstmann MA, Aifantis I, Cimmino L, Frietze S, den Boer ML, Mullighan CG, Smyth GK, Dickins RA. Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome. J Exp Med 214, 773-791 (2017)
Witkowski MT*, Cimmino L*, Hu Y, Trimarchi T, Tagoh H, McKenzie MD, Best SA, Tuohey L, Willson TA, Nutt SL, Busslinger M, Aifantis I, Smyth GK, Dickins RA. Activated Notch signaling counteracts Ikaros tumor suppression in mouse and human T cell acute lymphoblastic leukemia. Leukemia 29, 1301-1311 (2015).
Liu GJ, Cimmino L, Jude JG, Hu Y, Witkowski MT, McKenzie MD, Kartal-Kaess M, Best SA, Tuohey L, Mullighan CG, Farrar MA, Nutt SL, Smyth GK, Zuber J, Dickins RA. Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia. Genes Dev 28, 1337-1350 (2014).
Takiguchi M, Dow LE, Prier JE, Carmichael CL, Kile BT, Turner SJ, Lowe SW, Huang DCS, Dickins RA. Variability of inducible expression across the hematopoietic system of tetracycline transactivator transgenic mice. PLoS ONE 8, e54009 (2013).
Dickins RA, McJunkin K, Hernando E, Premsrirut PK, Krizhanovsky V, Burgess DJ, Kim SY, Cordon-Cardo C, Zender L, Hannon GJ, Lowe SW. Tissue-specific and reversible RNAi in transgenic mice. Nat Genet 39, 914-921 (2007).
Dickins RA, Hemann MT, Zilfou JT, Simpson DR, Ibarra I, Hannon GJ, Lowe SW. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nat Genet 37, 1289-1295 (2005).
Former lab members
Margherita Ghisi, PhD: Postdoctoral fellow, 2015-2016
Currently Postdoctoral fellow, Toulouse, France
Minhee Halemba, BSc(Hons): Research assistant 2014-2015
Currently PhD student, Monash University, Melbourne
Michael Erlichster, BSc(Hons): Honours student 2013
Currently PhD student, University of Melbourne
Mutlu Kartal-Kaess, MD PhD: Postdoctoral Fellow 2010-2013
Currently Medical Specialist, Heidelberg, Germany
Matthew Witkowski, PhD: Honours student 2011, PhD student 2012-2015
Currently Postdoctoral Fellow, NYU, USA
Mark McKenzie, PhD: Postdoctoral fellow 2010-2015
Currently Postdoctoral fellow, WEHI, Melbourne
Laura Tuohey, BMS/BBT: Research assistant 2010-2011
Currently Research assistant, University of Melbourne
Luisa Cimmino, PhD: Postdoctoral fellow 2008-2011
Currently Assistant Professor, NYU, USA
Megumi Takiguchi, PhD: Postdoctoral fellow 2009-2012
Currently Dentist, Perth
Grace Liu, PhD: PhD student 2010-2014
Currently Postdoctoral fellow, IMP, Vienna
Rachael Lane: Research assistant 2008-2012
Currently Research assistant, WEHI, Melbourne
Sarah Best, PhD: Research assistant 2008, Honours student 2009
Currently Postdoctoral fellow, WEHI, Melbourne