Leukaemia Modelling and Therapeutic Discovery
Research Group Head
Acute Myeloid Leukaemia (AML) is an aggressive blood cancer resulting from the uncontrolled proliferation and impaired function of immature myeloid cells in the bone marrow. Each year ~1000 Australians are diagnosed with AML, with more than half ultimately succumbing to their disease within 5 years. Chemotherapy remains the backbone of AML treatment, and while the majority of patients initially achieve remission with chemotherapy, many will ultimately relapse with chemo-resistant disease. New therapeutic strategies are desperately needed.
The Leukaemia Modelling and Therapeutic Discovery research group uses leukaemia modelling approaches to identify common molecular and biological dependencies of transformed myeloid cells, which may represent new therapeutic targets with broad applicability across diverse genetic subtypes. The ultimate goal of this research is to identify and develop new treatment opportunities for AML patients that will enhance overall survival and reduce the impact of this aggressive blood cancer on patients, carers and family members.
- Acute Erythroid Leukaemia (AEL) is a particularly aggressive and poorly understood subtype of AML that targets the red blood cell lineage. We have recently contributed to the world’s first complete genomic characterisation of AEL, and now have a unique understanding of the genetic mutations that define this malignancy. Through the generation of in vivo and in vitro genetic models that faithfully recapitulate the mutational landscape of human AEL, we aim to shed light on the mechanisms driving erythroid transformation and identify novel therapeutic strategies for patients with this disease.
- The Epithelial-Mesenchymal Transition (EMT) is a key developmental process that plays an important role during epithelial tumour development and pathogenesis. Activation of EMT in tumour cells contributes to the development of the migratory and invasive phenotype required for effective tumour cell metastasis. We and others have recently discovered that altered expression of key regulators of the EMT process also plays a critical role in the development and pathogenesis of Acute Leukaemia. Focusing on the EMT modulator, SNAI1, our lab aims to identify the key mechanisms used by SNAI1 to drive AML pathogenesis, and develop new ways of targeting SNAI1 in AML.
Projects and Opportunities
- Investigation of ETS-transcription factor function during normal and aberrant red blood cell development
- Generation of genetic models of Acute Erythroid Leukaemia
- Targeting EMT modulators in AML
- Generation and characterisation of iPS cells from Actue Leukaemia patient samples
Carmichael CL, Wang J, Nguyen T, Kolawole O, Benyoucef A, De Mazière C, Milne AR, Samuel S, Gillinder K, Hediyeh-Zadeh S, Vo ANQ, Huang Y, Knezevic K, McInnes WRL, Shields BJ, Mitchell H, Ritchie ME, Lammens T, Lintermans B, Van Vlierberghe P, Wong NC, Haigh K, Thoms JAI, Toulmin E, Curtis DJ, Oxley EP, Dickins RA, Beck D, Perkins A, McCormack MP, Davis MJ, Berx G, Zuber J, Pimanda JE, Kile BT, Goossens S, Haigh JJ (2020) The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1. Blood, 136:957-973.
Fagnan A, Bagger FO, Piqué-Borràs MR, Ignacimouttou C, Caulier A, Lopez CK, Robert E, Uzan B, Gelsi-Boyer V, Aid Z, Thirant C, Moll U, Tauchmann S, Kurtovic-Kozaric A, Maciejewski J, Dierks C, Spinelli O, Salmoiraghi S, Pabst T, Shimoda K, Deleuze V, Lapillonne H, Sweeney C, De Mas V, Leite B, Kadri Z, Malinge S, de Botton S, Micol JB, Kile B, Carmichael CL, Iacobucci I, Mullighan CG, Carroll M, Valent P, Bernard OA, Delabesse E, Vyas P, Birnbaum D, Anguita E, Garçon L, Soler E, Schwaller J, Mercher T (2020) Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers. Blood, 136:698-714.
Iacobucci I, Wen J, Meggendorfer M, Choi JK, Shi L, Pounds SB, Carmichael CL, Masih KE, Morris SM, Lindsley RC, Janke LJ, Alexander TB, Song G, Qu C, Li Y, Payne-Turner D, Tomizawa D, Kiyokawa N, Valentine M, Valentine V, Basso G, Locatelli F, Enemark EJ, Kham SKY, Yeoh AEJ, Ma X, Zhou X, Sioson E, Rusch M, Ries RE, Stieglitz E, Hunger SP, Wei AH, To LB, Lewis ID, D’Andrea RJ, Kile BT, Brown AL, Scott HS, Hahn CN, Marlton P, Pei D, Cheng C, Loh ML, Ebert BL, Meshinchi S, Haferlach T, Mullighan CG (2019) Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nat Genet, 51:694-704.
Thirant C, Ignacimouttou C, Lopez CK, Diop M, Le Mouël L, Thiollier C, Siret A, Dessen P, Aid Z, Rivière J, Rameau P, Lefebvre C, Khaled M, Leverger G, Ballerini P, Petit A, Raslova H, Carmichael CL, Kile BT, Soler E, Crispino JD, Wichmann C, Pflumio F, Schwaller J, Vainchenker W, Lobry C, Droin N, Bernard OA, Malinge S, Mercher T (2017) ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. Cancer Cell, 31:452-465.
Tang JZ, Carmichael CL, Shi W, Metcalf D, Ng AP, Hyland CD, Jenkins NA, Copeland NG, Howell VM, Zhao ZJ, Smyth GK, Kile BT, Alexander WS (2013) Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia. Proc Natl Acad Sci U S A, 110:6091-6096.
Carmichael CL, Metcalf D, Henley KJ, Kruse EA, Di Rago L, Mifsud S, Alexander WS, Kile BT (2012) Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia. Proc Natl Acad Sci U S A, 109:15437-15442.
Hahn CN, Chong CE*, Carmichael CL*, Wilkins EJ, Brautigan PJ, Li XC, Babic M, Lin M, Carmagnac A, Lee YK, Kok CH, Gagliardi L, Friend KL, Ekert PG, Butcher CM, Brown AL, Lewis ID, To LB, Timms AE, Storek J, Moore S, Altree M, Escher R, Bardy PG, Suthers GK, D’Andrea RJ, Horwitz MS, Scott HS (2011) Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet, 43:1012-1017. *Equal contribution.
Ng AP, Hyland CD, Metcalf D, Carmichael CL, Loughran SJ, Di Rago L, Kile BT, Alexander WS (2010) Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome. Blood, 115:3966-3969.
Carmichael CL, Majewski IJ, Alexander WS, Metcalf D, Hilton DJ, Hewitt CA, Scott HS (2009) Hematopoietic defects in the Ts1Cje mouse model of Down syndrome. Blood, 113:1929-1937.