Research units - Haematology and Leukaemia

Haematology and Leukaemia

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We study normal blood maturation of the T, B and myeloid lineages. Additionally, we are developing mouse models of abnormal blood maturation such as lymphoma and leukaemia.

Research Overview

The laboratory is pursuing mouse models of lymphoma and myeloid leukaemia. An emerging theme in leukaemia is the concept of a leukaemic stem cell (LSC). It is hypothesised that the LSC is the origin of the leukaemic disease and that therapies directed at its eradication will be more successful than previous approaches as it strikes at the potential heart of the leukaemia. With the advent of specific mAb and high speed flow cytometry it has now become possible to isolate very small subsets of bone marrow subpopulations that are responsible for development of all the different blood lineages.

We are using this technology to ultimately identify LSC in mouse models of lymphoma and myeloid leukaemia. Once identified, the LSC will be molecularly compared to its normal counterpart to identify the genes which allow the LSC to self-renew and propagate disease. These genes can ultimately be used as targets to design drugs which are more specific and possess less side effects than current therapies.

Research Themes

T cell development and T cell leukaemia/lymphoma

A novel model of mouse myeloid leukaemia

Oncogene discovery using a genetic screen

Honours and PhD Projects

Staff

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Dr David Izon
Dr Monique Smeets
Dr Sita Dewamitta

Publication Highlights

  1. Bain, G., Robanus-Maandag, E.C., Izon, D.J., Amsen, D., Kruisbeek, A.M., Weintraub, B., Krop, I., Schissel, M.S., Feeney, A.J., van Roon, M., van der Walk, M., te Riele, H.P.J., Berns, A. and Murre, C. 1994. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell. 79, 885-892.
  2. Verbeek, S , Izon, D.J.,  Hofhuis, F., Robanus-Maandag, E., te Riele, H., van de Wetering, M., Oosterwegel, M., Wilson, A., MacDonald, H.R., and Clevers, H.1995. Requirement of HMG Box factor Tcf-1 for thymocyte differentiation. Nature. (London), 374, 70-74.
  3. Izon, D.J., Rozenfeld, S., Fong, S., Komuves, L.G.,  Largman, C., and Lawrence, H.J. 1998. Loss of function of the homeobox gene Hoxa-9  perturbs early T cell development and induces apoptosis in primitive thymocytes. Blood. 92: 383-393.
  4. Izon, D.J., Punt, J.A., Xu, L., Karnell, F.G., Allman, D., Myung, P.S., Boerth, N.J., Pui, J.C. Koretzky, G.A. and Pear, W.S. 2001. Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength. Immunity.14:253-264. 
  5. Izon, D.J., Rudd, K., DeMuth, W., Pear, W.S., Clendenin,  C., Lindsley, R.C.,  and Allman, D. 2001. A common pathway for dendritic cell and B cell development. J.Immunol. 167:1387-1392.
  6. Izon, D.J., Aster, J.C., He, Y., Weng, A ., Karnell, F.G., Patriub, V., Xu, L., Bakkour, S., Rodriguez, C., Allman, D., and Pear, W.S. 2002. Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity.16:231-243.
  7. Glaser, S. Metcalf, D. Wu, L., Hart, A.H., DiRago, L., Mifsud, S., D’Amico, A., Dagger, S., Campo, C., Chan, A.C., *Robb, L., and *Izon, D.J. 2006. Enforced expression of the homeobox gene Mixl1 impairs hematopoietic differentiation and results in acute myeloid leukemia. Proc. Natl. Acad. Sci. (USA) 103(44):16460-16465. *=equal chief investigators.
  8. Gothert JR, Brake RL, Smeets M, Duhrsen U, Begley CG, Izon D.J. 2007.
  9. NOTCH1 pathway activation is an early hallmark of SCL T-leukemogenesis. Blood.110(10):3753-62.
  10. Chan, A.C, Smeets, M.F, Izon DJ. 2008. An in vivo functional genetic screen for suppressors of the Rag1(-/-) T-cell defect. Mol. Immunol.45(3):682-9.
  11. Izon, D.J. Thymus settling cells: Settled? 2008. Immunol. Cell. Biol. 86: 552-553. Invited Commentary.