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. We are also investigating related diseases in the Myeloproliferative neoplasm (MPN) disease group. MPN are a group of chronic diseases characterised by high blood cell counts, increased risk of bleeding and clotting, and a propensity to transform to AML.
The research carried out by the Acute Leukaemia Laboratory strives to better understand the mechanisms underlying these diseases, 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, 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.
Current research projects
- DNA repair. DNA repair pathways play a critical role in cancer initiation and progression. Our recent studies have linked the Fanconi Anaemia DNA repair genes to an increased risk of AML and we are now investigating the effects of heterozygous damaging mutations in these genes with a view to understanding the subtle changes induced that contribute to development of leukaemia. We are also studying the tumour suppressor gene GADD45A 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. Our focus for these projects is to understand the mechanism of DNA methylation and silencing, and also the link between the DNA methylation at the GADD45A promoter and poor outcome for AML patients receiving standard chemotherapy.
- 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 collaborative initiative investigating the clinical potential of a number of novel small molecule inhibitors in AML, using patient samples and assays for targeting of leukaemic stem cells.
- Non-coding RNAs in AML. Despite findings that recurrent changes to protein-coding genes occur in AML, and are directly linked to pathogenesis, the contribution of non-coding genes (ncRNA) to disease biology and treatment is still largely unclear. The ncRNAs are emerging as key regulators of an increasing number of molecular processes, with their aberrant expression being correlated with the development of cancers and with clinical outcome. We are collaborating with a number of research groups to determine the relationships between ncRNA expression, common AML mutations, disease characteristics and outcome. The data from our study will be important for the adoption of ncRNAs as clinical biomarkers to improve AML diagnosis, and will also guide our continuing targeted experimental investigations of novel genes that are dysregulated in AML.
- 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 novel somatic gene variants that highlight pathways of importance in MPN pathogenesis and are working to determine the functional significance of these using models of MPN. In addition, we are investigating new therapeutic approaches to targeting the primitive disease-initiating cells in myelofibrosis, a disease for which better treatment is required to halt disease progression.
Clinical trials in AML. Clinical trials provide AML patients with access to new treatments. Our laboratory undertakes studies in conjunction with the Haematology Clinical Trials Unit in the Royal Adelaide Hospital to identify factors linked to response, and to test these as biomarkers for patient stratification and therapy response.
Maung KZY, Leo PJ, Bassal M, Casolari DA, Gray JX, Bray SC, Pederson S, Singhal D, Samaraweera SE, Nguyen T, Cildir G, Marshall M, Ewing A, Duncan EL, Brown MA, Saal R, Tergaonkar V, To LB, Marlton P, Gill D, Lewis I, Deans AJ, Brown AL, D'Andrea RJ, Gonda TJ. Rare variants in Fanconi anemia genes are enriched in acute myeloid leukemia. Blood Cancer J. 2018 Jun 1;8(6):50.
Beck D, Thoms JAI, Palu C, Herold T, Shah A, Olivier J, Boelen L, Huang Y, Chacon D, Brown A, Babic M, Hahn C, Perugini M, Zhou X, Huntly BJ, Schwarzer A, Klusmann JH, Berdel WE, Wörmann B, Büchner T, Hiddemann W, Bohlander SK, To LB, Scott HS, Lewis ID, D'Andrea RJ, Wong JWH, Pimanda JE. A four-gene LincRNA expression signature predicts risk in multiple cohorts of acute myeloid leukemia patients. Leukemia. 2018 Feb;32(2):263-272.
Casolari DA, Nguyen T, Butcher CM, Iarossi DG, Hahn CN, Bray SC, Neufing P, Parker WT, Feng J, Maung KZY, Wee A, Vidovic L, Kok CH, Bardy PG, Branford S, Lewis ID, Lane SW, Scott HS, Ross DM, D'Andrea RJ. A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm. Scientific Reports 7(1):2467, 2017
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 MJM, Zantomio D, Scott HS, D'Andrea RJ, Hahn CN, Ross DM. Apparent 'JAK2-negative' polycythaemia vera due to compound mutations in exon 14. Br J Haematol. 2017 Jul;178(2):333-336.
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.