Poster Presentation 27th Lorne Cancer Conference 2015

The role of the polarity protein, Par3, in haematopoiesis. (#155)

Alysha Dew 1 2 , Naomi Campanale 1 2 , Yih-Chih Chan 1 2 , Judy Borg 1 , Rachel Bower 3 , Leah Adolph 1 2 , Sarah Russell 1 2 4 , Sarah Ellis 1 2
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  3. Box Hill Institute, Box Hill, Victoria, Australia
  4. Swinburne University of Technology, Hawthorn, Victoria, Australia

The polarity protein, Par3, is a member of the Par (Partitioning Defective) polarity complex. Par3 acts in a context dependent manner as either a tumour suppressor or an oncogene in a number of human epithelial cancers including breast, skin, and renal cancers. However, the role of Par3 in haematopoietic cancers has not been explored. Another polarity protein, lethal giant larvae homologue 1 (Llgl1), has recently emerged as a regulator of haematopoietic stem cell proliferation and decreased levels of Lgl1 are associated with inferior survival in patients with acute myeloid leukaemia (Heidel et al 2013). Polarity proteins are critical for the migratory capacity of T cells and in the formation of the immunological synapse (Ludford-Menting et al 2005). Based on these data, we hypothesise that Par3 is important during haematopoiesis and leukaemia progression. Using multiple approaches, we reveal Par3 is expressed in haematopoietic progenitors and their more differentiated progeny. Inducible Par3 knockout mice showed loss of Par3 results in a significant increase in the proportion of multipotent progenitors and in both the proportion and absolute number of common myeloid progenitors. Interestingly, whilst the proportion of early B cell progenitors was similar between Par3 knockout and littermate controls, the numbers of these cells was significantly increased in the Par3 knockout mice. These changes were associated with increased levels of pERK in the bone marrow of Par3 knockout mice and an increase in apoptosis within the common myeloid progenitor compartment. Taken together our data reveal Par3 is an important regulator of the haematopoietic system, with the potential to be involved in the development and progression of haematopoietic malignancies.

  1. Heidel, F.H., Bullinger, L., Arreba-Tutusaus, P., Wang, Z., Gaebel, J., Hirt, C., Niederwieser, D., Lane, S.W., Döhner, K., Vasioukhin, V., et al. (2013). The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML. The Journal of Experimental Medicine 210, 15-22.
  2. Ludford-Menting, M.J., Oliaro, J., Sacirbegovic, F., Cheah, E.T., Pedersen, N., Thomas, S.J., Pasam, A., Iazzolino, R., Dow, L.E., Waterhouse, N.J., et al. (2005). A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity 22, 737-748.