THE ROLE OF THE POLARITY PROTEIN PAR3 IN HAEMATOPOIESIS AND LEUKAEMIA

Cell polarity is a critical feature of multiple aspects of cell biology e.g. cell division and differentiation. Disrupted polarity network is well established in epithelial cancers where the polarity regulators act as tumour-suppressors or oncogenes. In the haematopoietic system, polarity proteins regulate asymmetric cell division (ACD) of haematopoietic stem cells (HSCs). ACD is central to the maintenance of normal haematopoiesis, ensuring the retention of self-renewal and differentiation potentials of HSCs. Disrupted ACD is associated with leukaemia transformation as leukemic cells lose the ability to differentiate and instead gain the ability to self-renew. Considering this and the role of polarity proteins in ACD, understanding how they regulate HSCs ACD or contribute to leukaemia is of major importance. We examined the role of polarity protein PAR3 in acute myeloid leukaemia (AML). To determine the role of PAR3 loss in haematopoiesis, we utilised a Par3 conditional knockout mouse model. For the human model, Par3 was knocked out in AML cell lines using CRISPR/Cas9. We found that PAR3 is differentially expressed in haematopoietic progenitors and their more differentiated progeny. PAR3 loss in a pre-clinical model of murine AML led to a significant increase in the proportion and number of granulocyte/macrophage progenitors, which are the hyperproliferative cancer stem cells. This was associated with deregulation of MAPK and HIPPO signalling pathways in PAR3 KO animals. To study the cellular and molecular mechanisms of PAR3 in human AML, we have successfully knocked out the Par3 in several human AML cell lines. The role of PAR3 in ACD is being studied by examining the cell cycle status using live cell imaging, cell differentiation, polarised inheritance of cell fate determinants, and mitotic spindle positioning. In conclusion, PAR3 acts as a tumour suppressor in AML.