Poster Presentation 30th Lorne Cancer Conference 2018

PAR3 loss predisposes mice to developing acute myeloid leukaemia via dysregulation of the Hippo pathway (#146)

Alysha Dew 1 , Aimie Lim 1 , Novita Novita 1 , Judy Borg 1 , Chad Johnson 2 , Cameron Skinner 1 , Carl Walkley 3 4 , Louise Purton 3 4 , Sarah Ellis 1
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Monash University, Clayton, VIC, Australia
  3. St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  4. Department of Medicine, St Vincent's Hospital, Fitzroy, VIC, Australia

The loss or deregulation of cell polarity is a hallmark of epithelial cancers. Three polarity complexes, the Par, Scrib, and Crumbs complexes, maintain apicobasal polarity in epithelial cells through mutual exclusion. PAR3, a key component of the Par polarity complex, is a scaffolding protein that interacts with multiple oncogenic intracellular signalling pathways through three PDZ protein-binding domains. PAR3 acts as a tumour suppressor or promoter in multiple different epithelial cancers in a cell and physiological context dependent manner. However, the role of PAR3 in haematopoiesis and haematopoietic malignancies is unknown. Utilising extensive phenotypic labelling regimes in conjunction with multicolour flow cytometry, we have shown that loss of PAR3 in conditional knockout mice heterozygous for Pten results in a significant increase in the proportion and number of granulocyte and macrophage progenitors (GMP), which are the cells that undergo tumorigenic transformation in acute myeloid leukaemia (AML). Reverse Phase Protein Array (RPPA) analyses identified proteins that are deregulated upon loss of PAR3 including the co-transcriptional activators of the Hippo signalling pathway, YAP and TAZ. Deregulation of the Hippo pathway leads to an increase in cell proliferation and a decrease in apoptosis and is receiving considerable attention as a putative therapeutic target. YAP and TAZ were significantly up-regulated in the bone marrow of experimental (Pten het Par3 KO) mice compared to controls and coincided with a significant increase in proliferation as indicated by Ki67 immunohistochemistry. In wild type bone marrow PAR3 and YAP were predominantly co-localised in the nucleus suggesting PAR3 is an important component of this pathway in haematopoietic cells. Taken together, our data reveals a novel mechanism of tumour suppression by PAR3 in a pre-clinical murine model of AML.