Mansour, MR; (2013) Role of the Notch signalling pathway in acute leukaemia. Doctoral thesis , UCL (University College London).

Preview

PDF Mansour_Final_thesis_copyrights_removed.pdf Download (5MB)

Abstract

The Notch signalling pathway is important in development and differentiation of a diverse range of both embryonic and adult tissues. There is now strong evidence implicating aberrant Notch signalling in the pathogenesis of T-cell acute lymphoblastic leukaemia (T-ALL), with over 50% of paediatric patients having activating mutations in NOTCH-1. This thesis aims to explore several aspects of the Notch pathway in both T-ALL and acute myeloid leukaemia (AML). Chapter one summarises the published data on the Notch signalling pathway itself, addressing the basic understanding of Notch activation through cell-to-cell interaction, as well as the mechanisms through which it is regulated. The role that Notch signaling plays in normal haematopoiesis is also discussed. Chapter three addresses the incidence and characteristics of NOTCH-1 mutations in a cohort of adult patients with T-ALL in comparison to the published study of paediatric T-ALL, as well as in a cohort of patients with infantile leukaemia and AML. Secondly, the prognostic significance of NOTCH-1 and FBXW7 mutation status of adult T-ALL patients treated on the UKALLXII was investigated. Thirdly, a novel mutation affecting the LNR domain of NOTCH-1 is reported. Chapter four includes data quantifying NOTCH-1 mutation level in T-ALL patients, as well as the stability of NOTCH-1 mutations at presentation and relapse. These data indicate NOTCH-1 mutations commonly occur as secondary events in leukaemia pathogenesis, and suggest widespread clonal heterogeneity in T-ALL. Chapter five explores the functional and prognostic consequences of a novel alternatively spliced isoform of the CSL transcription factor in AML, which was termed CSL-TREX (for TRuncates Exon X). The functional consequences of expressing CSL-TREX in CD34+ cells, in luciferase reporter assays and co-immunoprecipitation experiments with NOTCH-1 is reported. Chapter six summarises the overall implications of these findings to T-ALL and AML, and the future directions of research in this area.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item