Abstract
A key feature of epithelial cancers is loss of cell polarity. Polarity in epithelial cells is maintained by three complexes, the Par, Scribble, and Crumbs complexes. PAR3, a key component of the Par polarity complex, acts as a tumour suppressor or promoter in a cell and physiological context dependent manner in epithelial cancers. However, the role of PAR3 in hematopoiesis and hematopoietic malignancies is unknown. We utilised different Par3 conditional knockout mouse models in conjunction with an extensive phenotypic labelling regime and flow cytometry to investigate the role of PAR3 in leukemogenesis. We show loss of PAR3 in experimental mice conferred a strong predisposition to acute myeloid leukemia (AML) as evidenced by a significant increase in Granulocyte/Macrophage progenitors (GMP). In line with these results, interrogation of the TCGA data set revealed AML patients with low levels of PARD3 have a significantly worse prognosis. Reverse Phase Protein Array (RPPA) analyses revealed significant up-regulation of the Hippo downstream transcriptional activator, Yes-associated protein (YAP), in experimental animals compared to controls. Immunohistochemistry confirmed RPPA results and showed YAP was significantly up-regulated in the bone marrow of experimental mice compared to controls and coincided with a significant increase in proliferation as indicated by Ki67 staining. PAR3 and YAP predominantly co-localised in the nucleus further implicating PAR3 as an important component of the Hippo pathway. RNAseq in conjunction with PCR arrays are being conducted to reveal other Hippo family members deregulated in experimental mice compared to controls and we are using 7-color multiplex immunohistochemistry to identify alterations in the spatial distribution and physiology of GMP in the bone marrow upon loss of PAR3. Collectively, our studies will enhance our understanding of how PAR3 suppresses AML and may reveal potential therapeutic targets.
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