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The role of protein kinase C epsilon in the pathogenesis and treatment resistance of Acute Myeloid Leukaemia

Nicholson, Rachael Louise 2021. The role of protein kinase C epsilon in the pathogenesis and treatment resistance of Acute Myeloid Leukaemia. PhD Thesis, Cardiff University.
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Acute myeloid leukaemia (AML) is a heterogeneous group of haematological malignancies, characterised by the accumulation of abnormally differentiated blast cells in the bone marrow. For most patients, prognosis remains poor due to the prevalence of relapse. Protein kinase C epsilon (PKCε) is a pleiotropic regulator of cell signalling which has demonstrated oncogenic properties and in solid cancers, high PKCε expression is associated with poor outcomes. The aim of this study was to determine the clinical significance and functionality of PKCε in AML. Existing protein expression data showed that PKCε was significantly upregulated in 37% (26/70) of AML patient samples and was associated with reduced CR (p<0.05). To support this, I analysed an independent mRNA dataset where high PKCε expression correlated with significantly reduced overall (p<0.05) and disease-free survival (p<0.05). Together these data suggest that high PKCε expression is associated with poor outcomes in AML. Functionality was investigated by modulating PKCε in normal human haematopoietic cells where PKCε overexpression promoted monocyte differentiation. This finding is inconsistent with a role in leukaemogenesis. Instead, it was hypothesized that PKCε may promote chemoresistance. In two AML cell lines, PKCε overexpression conferred daunorubicin (DNR) resistance (p<0.05) without affecting cytarabine sensitivities. This was accompanied by reduced DNR accumulation, and the upregulation of the selective DNR efflux pump, P-GP. P-GP inhibition restored DNR accumulation and sensitivity, demonstrating P-GP drug efflux as the mechanism of PKCε-mediated DNR resistance. PKC agonist and inhibitor treatments suggested that PKCε modulates P-GP drug efflux through indirect mechanisms, but a correlation between PKCε and P-GP expression and function was supported by analysis of patient samples. However, reducing PKCε expression did not sensitize AML cells to DNR, potentially due to redundancy between PKC isoforms. In conclusion, elevated PKCε expression is a poor prognostic indicator in AML. Functional studies did not support an oncogenic role for PKCε in normal haematopoietic cells or AML cell lines. Nonetheless, PKCε can influence the chemosensitivity of AML cells by promoting P-GP-mediated DNR efflux, providing a mechanism through which PKCε could contribute to poor outcomes in this malignancy.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 7 May 2021
Last Modified: 06 May 2022 01:30

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