The Acute Leukaemia Laboratory has a fundamental interest in Acute Myeloid Leukaemia (AML). This devastating disease is the most common form of acute leukaemia in adults and is responsible for one fifth of all childhood leukaemia cases. AML comprises several subtypes, characterised by different combinations of genetic aberrations and prognostic outcomes. The genetic complexity of the disease has hampered progress in the field, with the molecular basis for some subtypes still largely unknown, and hence outcomes are still quite poor. Overall survival for adults with AML is still only 30-40%, and for some subtypes, prognosis is dismal, with a median overall survival of just 10 months. With the recent advances in genomics based applications, research in this field has been accelerated and we have been using some of these technologies to better understand the molecular aberrations responsible for this disease.
The research carried out by the Acute Leukaemia Laboratory strives to better understand the mechanisms underlying AML, with the ultimate goal of improving treatment outcomes. A significant research focus of the lab is the investigation of the mechanisms that control stem and progenitor cell growth and survival, and which are commonly deregulated in AML. We have used genetic and epigenetic approaches to identify novel genes and pathways important for AML pathogenesis and disease stratification, and to identify patients that may respond to novel, less toxic therapies. In addition, our research aims to understand the genetic changes that lead to the altered metabolism exhibited by AML cells. Finally, we are also interested in the role of the Epidermal Growth Factor Receptor (EGFR) in the Philadelphia Chromosome-negative Myeloproliferative Neoplasms (MPN), a group of chronic diseases associated with a predisposition for AML.
Current research projects
- Acute Myeloid Leukaemia Genomics: The use of high-resolution molecular methods, particularly high-throughput (next-generation) DNA sequencing in AML patient samples, is proving to be a powerful approach to identify leukaemic mutations and pathways. This can lead to the development of new markers for disease classification and prognosis, and may also identify molecular targets for novel therapeutics.
- Acute Myeloid Leukaemia metabolism: It has been known for the last 90 years that cancer cells have a distinct metabolic phenotype irrespective of originating tissue. Currently, we’re investigating how the metabolic phenotype of leukaemic cells is altered and how it relates to disease manifestation and progression. Most importantly, we’re investigating whether these metabolic alterations can be targeted therapeutically so as to provide better treatment options for patients.
- Testing New Therapies for Acute Myeloid Leukaemia: AML is a heterogeneous cancer both in terms of genetics and patient response to treatment. There is great need to develop novel and more selective treatment approaches targeting individual AML subtypes and patients who currently face very poor outcomes on standard therapy. This project represents a new cross-disciplinary collaborative initiative (with Prof. Shudong Wang; Centre for Drug Discovery & Development, and Prof. Richard Lock; Head of the Children’s Cancer Institute’s Leukaemia Biology Program) investigating the clinical potential of novel orally available kinase inhibitors in AML.
- Understanding the clinical and functional significance of GADD45A silencing by methylation in Acute Myeloid Leukaemia: GADD45A is a tumour suppressor gene that plays cell-type dependent roles in cellular stress co-ordinating DNA repair and de-methylation, cell cycle arrest, and pro-apoptotic or pro-survival responses. This project aims to determine the functional significance of silencing of GADD45A in AML with a particular focus on the mechanism of silencing and also the effect of silencing on the response to chemotherapeutics. Another aspect of this project involves assessing the utility of hypomethylating agents in reversing the silenced promoter of GADD45A, in order to assess whether treatment with hypomethylating agents could be targeted to patients with GADD45A hypermethylation.
- Molecular mechanisms of Polycythemia Vera – identification and characterisation of novel candidate genes: The Philadelphia chromosome negative myeloid proliferative neoplasms (MPN) are clonal stem cell disorders with an associated risk of progression to myelofibrosis and transformation to AML. We have identified several novel somatic gene variants that highlight novel pathways as potentially important in MPN pathogenesis and are working to determine the significance of these gene variants in MPN and AML.
Li S, Garrett-Bakelman FE, Chung SS, Sanders MA, Hricik T, Rapaport F, Patel J, Dillon R, Vijay P, Brown AL, Perl AE, Cannon J, Bullinger L, Luger S, Becker M, Lewis ID, To LB, Delwel R, Löwenberg B, Döhner H, Döhner K, Guzman ML, Hassane DC, Roboz GJ, Grimwade D, Valk PJ, D'Andrea RJ, Carroll M, Park CY, Neuberg D, Levine R, Melnick AM, Mason CE (2016). “Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia”. Nature Medicine. 22(7):792-9.
Shahrin NH, Diakiw S, Dent LA, Brown AL, D'Andrea RJ (2016). “Conditional knockout mice demonstrate function of Klf5 as a myeloid transcription factor”. Blood. 128(1):55-9.
Lynch JR, Yi H, Casolari DA, Voli F, Gonzales-Aloy E, Fung TK, Liu B, Brown A, Liu T, Haber M, Norris MD, Lewis ID, So CW, D'Andrea RJ, Wang JY (2016). Gaq signalling is required for the maintenance of MLL-AF9 induced AML. Leukemia. [Epub ahead of print]
Tiong IS, Casolari DA, Moore S, Nguyen T, Van Velzen MJ, Zantomio D, Scott HS, D'Andrea RJ, Hahn CN, Ross DM (2016). “Apparent 'JAK2-negative' polycythaemia vera due to compound mutations in exon 14”. Br J Haematol. [Epub ahead of print]
Lewinsohn M, Brown AL, Weinel LM, Phung C, Rafidi G, Lee MK, Schreiber AW, Feng J, Babic M, Chong CE, Lee Y, Yong A, Suthers GK, Poplawski N, Altree M, Phillips K, Jaensch L, Fine M, D'Andrea RJ, Lewis ID, Medeiros BC, Pollyea DA, King MC, Walsh T, Keel S, Shimamura A, Godley LA, Hahn CN, Churpek JE, Scott HS (2016). “Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies”. Blood. 127(8):1017-23.
Forristal CE, Brown AL, Helwani FM, Winkler IG, Nowlan B, Barbier V, Powell RJ, Engler GA, Diakiw SM, Zannettino AC, Martin S, Pattabiraman D, D'Andrea RJ, Lewis ID, Levesque JP (2015). “Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML” Leukemia 29(10):2075-85.
Hahn CN, Ross DM, Feng J, Beligaswatte A, Hiwase DK, Parker WT, Ho M, Zawitkowski M, Ambler KL, Cheetham GD, Lee YK, Babic M, Butcher CM, Engler GA, Brown AL, D'Andrea RJ, Lewis ID, Schreiber AW, To LB, Scott HS (2015). “A tale of two siblings: two cases of AML arising from a single pre-leukemic DNMT3A mutant clone”. Leukemia 29(10):2101-4.
Li S, Garrett-Bakelman F, Perl AE, Luger SM, Zhang C, To BL, Lewis ID, Brown AL, D'Andrea RJ, Ross ME, Levine R, Carroll M, Melnick A, Mason CE (2014). “Dynamic evolution of clonal epialleles revealed by methclone”. Genome Biol. 15(9):472.
Sadras T, Perugini M, Kok CH, Iarossi DG, Heatley SL, Brumatti G, Samuel MS, To LB, Lewis ID, Lopez AF, Ekert PG, Ramshaw HS, D'Andrea RJ (2014). “Interleukin-3-mediated regulation of β-catenin in myeloid transformation and acute myeloid leukemia”. J Leukoc Biol. 96(1):83-91.
Tan P, Wei A, Mithraprabhu S, Cummings N, Liu HB, Perugini M, Reed K, Avery S, Patil S, Walker P, Mollee P, Grigg A, D'Andrea R, Dear A, Spencer A (2014). “Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome”. Blood Cancer J. 4:e170.