Mammalian Functional Genetics
Leukaemia, Haematopoiesis, Erythroid Cell Biology, Genetics, Mouse Models
Acute Myeloid Leukaemia (AML) is a genetically heterogeneous malignancy that continues to have a poor overall survival rate despite extensive research in this area. While chemotherapeutic regimens are effective in inducing complete remission in approximately 70% of patients younger than 60 years of age, more than 40% of all AML patients will ultimately succumb to relapsed or therapeutically refractory disease. The Mammalian Functional Genetics group aims to use in vivo and in vitro genetic models of AML to identify common molecular and biological dependencies of transformed myeloid cells, which may represent novel therapeutic targets with broad applicability across diverse genetic subtypes.
Current Research Overview
Our current research focuses on Acute Erythroid Leukaemia (AEL), which 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 lesions 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.
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
- Generation and characterisation of iPS cells from Acute Leukaemia patient samples
- Genomic subtyping and therapeutic targeting of acute erythroleukemia. Iacobucci, I., J. Wen, M. Meggendorfer, J. K. Choi, L. Shi, S. B. Pounds, C.L. Carmichael, K. E. Masih, S. M. Morris, R. C. Lindsley, L. J. Janke, T. B. Alexander, G. Song, C. Qu, Y. Li, D. Payne-Turner, D. Tomizawa, N. Kiyokawa, M. Valentine, V. Valentine, G. Basso, F. Locatelli, E. J. Enemark, S. K. Y. Kham, A. E. J. Yeoh, X. Ma, X. Zhou, E. Sioson, M. Rusch, R. E. Ries, E. Stieglitz, S. P. Hunger, A. H. Wei, L. B. To, I. D. Lewis, R. J. D'Andrea, B. T. Kile, A. L. Brown, H. S. Scott, C. N. Hahn, P. Marlton, D. Pei, C. Cheng, M. L. Loh, B. L. Ebert, S. Meshinchi, T. Haferlach and C. G. Mullighan. Nat Genet 2019;51(4):694-704
- ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. 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. Cancer Cell. 2017 Mar 13;31(3):452-465.
- Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia. Tang, J.Z., Carmichael C.L, Shi, W., Metcalf, D., Ng, A.P., Hyland, C.D., Jenkins, N.A., Copeland, N.G., Howell, V.M., Zhao, Z.J., Smyth, G.K., Kile, B.T. & Alexander, W.S. (2013). Proc Natl Acad Sci U S A 110: 6091-6096.
- Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia. Carmichael C.L., Metcalf, D., Henley, K.J., Kruse, E.A., Di Rago, L., Mifsud, S., Alexander, W.S. & Kile, B.T. (2012). Proc Natl Acad Sci U S A 109: 15437-15442.
- Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Hahn, C.N., Chong, C.E*., Carmichael C.L.*, Wilkins, E.J., Brautigan, P.J., Li, X.C., Babic, M., Lin, M., Carmagnac, A., Lee, Y.K., Kok, C.H., Gagliardi, L., Friend, K.L., Ekert, P.G., Butcher, C.M., Brown, A.L., Lewis, I.D., To, L.B., Timms, A.E., Storek, J., Moore, S., Altree, M., Escher, R., Bardy, P.G., Suthers, G.K., D'Andrea, R.J., Horwitz, M.S. & Scott, H.S. (2011). Nat Genet 43: 1012-1017. *Equal contribution.
- Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome. Ng, A.P., Hyland, C.D., Metcalf, D., Carmichael C.L., Loughran, S.J., Di Rago, L., Kile, B.T. & Alexander, W.S. (2010). Blood 115: 3966-3969.
- Hematopoietic defects in the Ts1Cje mouse model of Down syndrome. Carmichael C.L., Majewski, I.J., Alexander, W.S., Metcalf, D., Hilton, D.J., Hewitt, C.A. & Scott, H.S. (2009). Blood 113: 1929-1937.