Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) in Chronic Myeloid Leukaemia

Abstract

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in a haematopoietic stem cell (HSC) and defined by the presence of BCR-ABL1, a deregulated tyrosine kinase that drives numerous oncogenic signalling pathways. Current CML therapies are tyrosine kinase inhibitors (TKIs) that target the constitutive action of BCR-ABL1. However, resistance to TKIs remains a concern for a substantial proportion of CML patients and thus investigating the mechanisms underlying poor clinical response is of great importance. The tumour suppressor protein phosphatase 2A (PP2A) plays a crucial role in the inhibition of several critical oncogenic signalling pathways. Consequently, reports of aberrant PP2A activity in human malignancies are abundant. Cancerous inhibitor of PP2A (CIP2A) is an endogenous inhibitor of PP2A that is overexpressed in a plethora of tumours; CIP2A inhibits the dephosphorylation of the oncogenic transcription factor c-Myc by PP2A. In CML, it was shown that high CIP2A protein expression at diagnosis was predictive of progression into blast crisis in imatinib-treated CML. This thesis aimed to determine if CIP2A retained its potential prognostic indicator status in CML treated with dasatinib or nilotinib. The molecular pathogenesis of the CIP2A/PP2A pathway within CML and the central role played by CIP2A is also investigated. Molecular interactions of proteins have been known to greatly differ between transcript variants of the same gene. No CIP2A transcript variant has ever been reported. This thesis aimed to identify two CIP2A transcript variants previously undescribed in vivo, and analyse their differing expressions within a CML population. Aberrant epigenetic regulation is an expanding area of interest; many genes have their expression altered via deregulated methylation, transcription factor binding and micro RNAs. This thesis focussed on the methylation of the CIP2A promoter in CML of varying disease phase and clinical outcome. In summary, this thesis provides novel information about CIP2A in response to CML treatment, CIP2A protein interactions, CIP2A gene variations and epigenetic regulation. With more knowledge of this oncoprotein, its oncogenic mechanisms may in the future be specifically targeted and overcome.