About the Project
Clinical outcomes for acute myeloid leukaemia (AML) are still poor for the majority of patients which has led to a drive for targeted treatments (that can be used instead of, or in conjunction with, chemotherapeutic drugs). The molecular heterogeneity of this disease has led us to employ a number of omics platforms to identify proteins which (i) are aberrantly expressed in AML patients at high frequency; (ii) that are associated with poorer outcomes and (iii) that are potentially targetable with small molecules. Amongst these candidates, we have identified a serine/threonine kinase, protein kinase C epsilon (PKC-E) that fulfils all these criteria. Further, while the role of this protein in AML is completely unknown, it has been implicated in the pathogenesis of a variety of other cancers and is the only PKC enzyme shown to act as an oncogene.
While we have extensive correlative pre-publication data which support its role in this disease, we need now to describe its functional role in AML. The investigation will be centred on (i) its role in treatment-resistance (which preliminary data suggest may be mediated via BCL2) and (ii) its role in the pathogenesis of AML by analysing its effect on haematopoietic development and lineage specification (known to be influenced by other PKC enzymes). These are completely novel questions and will be addressed using appropriate models and methodologies firmly established in this laboratory with the capability to validate any findings in patient samples (for which clearance is already in place). There is enough scope and scientific rationale to broaden the project to encompass the effect of PKC-E on cytokine responses, migration and self-renewal, providing a contingency for change to the core research plan. Based on previous experience, data of this sort is publishable in high impact factor journals. The work will be supervised by a trained and experienced supervisory team with a track record of successful outcome in an excellent research environment for the study of blood cancer.
References
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