Ismail, Mohamed Araby (2021) Evaluation of protein tyrosine phosphatase receptor gamma (PTPRG) as a biomarker in chronic myeloid leukaemia patients in the State of Qatar. (PhD thesis), Kingston University, .
Abstract
Chronic Myeloid Leukaemia (CML) is a clonal myeloproliferative disorder characterized by a shortened chromosome 22 known as the Philadelphia chromosome (Ph). As the main transforming property of the Breakpoint Cluster Region- Abelson Murine Leukaemia 1 (BCR-ABL1) oncoprotein is mediated by its constitutive tyrosine kinase activity, direct inhibition of such activity seems to be the most straightforward means of silencing the oncoprotein. Indeed, Tyrosine Kinase Inhibitors (TKIs) has dramatically improved the outcomes in CML patients. However, a percentage of patients are treatment resistance. Internationally, over 25% of CML patients have resistance to treatments with the TKIs and this is around 54% in Qatar. It is therefore essential to identify biomarkers of prognostic significance, predictive value for the response to therapy and as targets for therapy. Dysregulation phosphorylation and dephosphorylation of protein by kinases and phosphatases are important in cancer. Of these, Protein Tyrosine Phosphatases (PTPs) are a group of enzymes that remove the phosphate groups derived from the Tyrosine kinase. One of these, Protein Tyrosine Phosphates Receptor Gamma (PTPRG) is known as tumour suppressor gene and found to be down regulated in CML. The aim of this PhD project was to examine expression level and predictive value of PTPRG as biomarker for the response to therapy with the small molecules tyrosine kinase inhibitors (TKIs) in CML patients in Qatar. The findings are consistent with the mainstream findings that the PTPRG has a natural inhibitory mechanism and it was found to be down regulated in CML patients. In addition, using anti-PTPRG monoclonal antibody TPγ B9-2, a unique flow cytometry technique was developed. It was able to record changes in the expression level of PTPRG at diagnosis and in particular its restoration following treatment with one of the BCR/ABL TKIs. Interestingly, the aberrant DNA methylation of PTPRG was found be one of the possible mechanisms of its under expression in CML patients. Furthermore, 7 PTPRG variants (4 annotated and 3 Novel) were found in this study and their expression was found to be significantly different between the TKI resistant cases compared to responders as well as healthy individuals. Finally, towards the end of this PhD project, CML biobanking was successfully established at Interim Translational Research Institute (iTRI) Doha-Qatar and this should open new spectrum in support of health care research strategies. All these findings and their importance will be discussed in this thesis.
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