The bone marrow microenvironemnt is essential for the function of connective tissue growth factor (CTGF/CCN2) in childhood accute lymphoblastic leukaemia

Julia Wells

    Research output: ThesisDoctoral Thesis

    549 Downloads (Pure)

    Abstract

    [Truncated] Acute lymphoblastic leukaemia (ALL) is the most commonly diagnosed cancer in children. Successive chemotherapy treatment protocols have been successful in increasing overall survival rates to 90%. However, further improvement is achievable only through a better understanding of the pathogenesis of ALL and the mechanisms of drug resistance. Connective tissue growth factor (CTGF/CCN2) has previously been reported as the most deregulated gene in childhood B-cell precursor (BCP) ALL, existing in approximately 75% of cases (Boag et al., 2007) and has been associated with a poor prognosis in both children and adults (Kang et al., 2010, Sala-Torra et al., 2005). A functional role for CTGF has yet to be determined in ALL, though in other cancers it’s deregulation contributes positively to tumour progression and survival.

    In this thesis the functional role of CTGF in childhood BCP ALL was explored in three ways. Firstly, two BCP ALL cell lines (PER-278 and PER-371, established from primary patient specimens) where engineered to stably express human CTGF and a GFP reporter coding sequence. Overexpression of CTGF in PER- 278 and PER-371 was confirmed by qRT-PCR (2.6 and 3.4 fold, respectively) and by western blot, for both cellular protein and conditioned media. In culture conditions, high levels of CTGF did not alter proliferation, drug sensitivity (to cytarabine and vincristine) or the gene expression profile of PER-278 or PER- 371. A marked difference was seen between the gene expression profiles of the two BCP ALL cell lines, resulting in different genes being co-expressed with CTGF and foreshadowing the cell line-specific interactions seen in the mouse bone marrow microenvironment.

    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2015

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