Jane/Curtis Group - Red Cell Research

Division of Blood Cancers

Goal

To identify regulators of red cell production and function including globin switching

Research Focus and Tools

  • Globin switching
  • ENU mutagenesis in the mouse

Research Overview

Globin switching - Defining the molecular mechanisms underpinning fetal (gamma) globin gene silencing may provide strategies for reactivation of gamma-gene expression, a major therapeutic objective in patients with beta-thalassemia and sickle cell disease. Our laboratory has identified and defined the NF-E2 transcription factor complex as a critical regulator of the beta globin locus. The laboratory is now focusing on the therapeutic potential of targeting PRMT5, a critical component of the complex that represses gamma globin.

ENU-mutagenesis - Chemical mutagenesis has been used to identify genetic pathways in lower organism for more than 20 years. We have recently used ENU mutagenesis in the mouse to generate mouse lines with defects in red blood cells. The laboratory has over 20 different mutant lines, revealing surprising insights into how red cells are produced and function

Projects and Opportunities

  • Protein arginine methyltransferase 5 – a new target for sickle cell disease and lymphoid malignancies
  • Using forward genetics to understand the regulation of red blood cells

For current project opportunity descriptions please visit our honours page


L-R: Fiona Brown, Stefan Sonderegger, David Curtis,
Stephen Jane, Loretta Cerruti

Lung section from an ENU mouse mutant of the phosphatase SHIP1 showing macrophages with eosinophilic Ym1 crystals

Selected Publications

  • Pawlak, M., Walkowska, A., Mlacki, M., Pistolic, J., Wrzesinski, T., Benes, V., Jane, S.M., Wesoly, J., Kompanowska-Jezierska, E., Wilanowski, T., 2015, Consequences of the loss of the Grainyhead-like 1 gene for renal gene expression, regulation of blood pressure and heart rate in a mouse model, Acta Biochimica Polonica [P], vol 62, issue 2, Polskie Towarzystwo Biochemiczne, Warsaw Poland, pp. 287-296.
  • Cummins, K., Jane, S.M., Ninkovic, S., Bazargan, M.A., Filshie, R.J.A., Sutrave, G., Hertzberg, M.S., Scott, A.A., Lane, S., Yannakou, C., Ritchie, D., D'Rozario, J.M., Black, J., Bavishi, K., Wei, A., 2014, Sorafenib priming may augment salvage chemotherapy in relapsed and refractory FLT3-ITD-positive acute myeloid leukemia, Blood Cancer Journal [E], vol 4, issue 8, Macmillan Publishers Limited, London N1 9XW, p. e237.
    Dworkin, S., Simkin, J.E., Darido, C., Partridge, D., Georgy, S., Caddy, J., Wilanowski, T., Lieschke, G., Doggett, K., Heath, J.K., Jane, S.M., 2014, Grainyhead-like 3 regulation of endothelin-1 in the pharyngeal endoderm is critical for growth and development of the craniofacial skeleton, Mechanisms of Development [P], vol 133, Elsevier Ireland Ltd, Ireland, pp. 77-90.
  • Mlacki, M., Darido, C., Jane, S.M., Wilanowski, T., 2014, Loss of grainy head-like 1 is associated with disruption of the epidermal barrier and squamous cell carcinoma of the skin, PLoS ONE [E], vol 9, issue 2
    (Art. ID: e89247), Public Library of Science, USA, pp. 1-9.
  • Brown, F., Scott, N., Rank, G., Collinge, J.E., Vadolas, J., Vickaryous, N., Whitelaw, N.C., Whitelaw, E., Kile, B., Jane, S.M., Curtis, D.J., 2013, ENU mutagenesis identifies the first mouse mutants reproducing
    human beta-thalassemia at the genomic level, Blood Cells Molecules And Diseases [P], vol 50, issue 2, Academic Press, United States, pp. 86-92.
  • Darido, C., Jane, S., 2013, Golgi feels its own wound, Advances in Wound Care [P], vol 2, issue 3, Mary Ann Liebert, United States, pp. 87-92.
    Dworkin, S., Jane, S.M., 2013, Novel mechanisms that pattern and shape the midbrain-hindbrain boundary, Cellular And Molecular Life Sciences [P], vol 70, issue 18, Birkhaeuser Verlag, Switzerland, pp. 3365-3374.

Current Funding

  • Globin NHMRC grant, CIA: Professor Stephen Jane. Total funding - $AUD 617,562
  • NHMRC project grant APP1086662 (2015-2018): Eradicating leukaemic stem cells by targeting the arginine methyltransferase PRMT5. PIs: Curtis, Jane, Haigh, Wei and Powell. Total funding - $AUD 742,353
  • Wellcome Trust Seeding Drug Discovery Award (2015-2017): Inhibitors of protein arginine methyltransferase 5 (PRMT5) for the treatment of β-thalassemia and sickle cell disease. PIs: Street, Jane and Curtis. Total funding - $AUD 244,740