Mr Mohamed Ismail

Research project: Evaluation the role of protein tyrosine phosphatase receptor Gamma (PTPRG) in tumour progression and as a biomarker in patients with chronic myelogenous leukaemia in the State of Qatar.

Abstract

Chronic Myelogenous leukaemia (CML) is a haematopoietic stem cell disorder that transforms normal stem cells to hyper-proliferated abnormal stem cells. CML is also characterised by various types of genetic alterations including mutation, deletion and translocation. Of these, a fusion gene termed BCR-ABL1 has been identified in most patients with CML. The expression of BCR-ABL1 oncoprotein results in the deregulated activation of its tyrosine kinase domain in patients with CML.

At present, three BCR-ABL TKIs namely Imatinib, Nilotinib and Dasatinib have been approved by the United States Food and Drug Administration (FDA) for the treatment of patients with CML. However, recent studies showed there are more than 50 kinase domain mutation sites and more than 70 different BCR-ABL1 mutations which can contribute to resistance to treatment with Imatinib, with point of mutations within the kinase domain being the most common and frequent mechanisms of resistance.

More recently 45% of CML patients who participated in the International Randomized Study of Interferon and STI571 (IRIS) failed to continue on Imatinib therapy at the 8-year follow-up time. Therefore, it is clear that not all patients with CML would gain long term benefit from therapy with TKIs and it is important to uncover the underlying mechanisms of resistance to therapy with the BCR-ABl TKIs.

In particular, it is important to study the role of tumor suppressor which has a negative regulatory effect on the phosphorylation process. Of these, protein tyrosine phosphatase receptor Gamma (PTPRG) is a candidate tumor suppressor gene and belong to receptor type protein tyrosine phosphatases (RPTPs).

The aim of this PhD is to conduct more detailed study of PTPRG at molecular level to determine whether PTPRG is genetically and epigenetically altered in CML and and such alterations can be of prognostic significance in patients with CML.