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Identifying novel therapeutic targets and prognostic markers through analysis of allele specific alterations in T-cell acute lymphoblastic leukaemia

Farah, Nadine Hani Rashad; (2021) Identifying novel therapeutic targets and prognostic markers through analysis of allele specific alterations in T-cell acute lymphoblastic leukaemia. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Although the survival of patients with Acute Lymphoblastic Leukaemia (ALL) has greatly improved, there is still a significant proportion of patients with T-cell ALL (T-ALL) who have refractory disease, and the outcome of patients who relapse is very poor. There is an unmet need to improve therapeutic strategies, and in this thesis I use the allelic alterations in T-ALL to address this. In Results Chapter 1, I undertake a molecular assay to establish the allelic status at the T-cell receptor gamma locus in paediatric patients with T-ALL treated on the UKALL2003 trial to identify the early T-cell precursor (ETP) group. I show that the T-ALL immaturity status does not have additional prognostic impact to that already derived by minimal residual disease risk-adapted therapy in this trial. In Results Chapter 2, I describe a new bioinformatic pipeline to discover genes with monoallelic expression in T-ALL that could be driven by a cis-acting lesion. I focus on PDGFRB identified by this pipeline as it is a well-established oncogene in other haematological malignancies with targeted therapy available in the clinic. I show that there are no genetic lesions in the 450kb region around PDGFRB, and the 2 CTCF sites 5kb-upstream of PDGFRB are not critical for its expression. In Results Chapter 3, I explore PDGFRβ as a therapeutic target in T-ALL and find that T-ALL cell lines expressing PDGFRB are sensitive to treatment with the tyrosine kinase inhibitor dasatinib. Western blot for PDGFRβ protein expression identifies a unique 80kDa band in the T-ALL cell line CTV-1 that has high PDGFRB expression. This band appears to be autophosphorylated, is sensitive to treatment with dasatinib, and is not explained by an aberrant PDGFRB transcription start site. In the final chapter, I summarise the results of this thesis and highlight the future directions for research.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Identifying novel therapeutic targets and prognostic markers through analysis of allele specific alterations in T-cell acute lymphoblastic leukaemia
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10137123
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