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Elucidation of molecular mechanism of TSP-1 induced cell growth inhibition in childhood acute lymphoblastic leukemia. / Elucidation of molecular mechanism of thrombospondin-1 induced cell growth inhibition in childhood acute lymphoblastic leukemia

Ng, Ka Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 118-131). / Abstracts in English and Chinese. / Thesis Abstract --- p.i / 論文摘要 --- p.vi / Acknowledgements --- p.x / Abbreviations --- p.xii / Thesis Content --- p.xv / List of Figures --- p.xix / List of Tables --- p.xxi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Haematopoiesis --- p.1 / Chapter 1.2 --- Leukemia --- p.2 / Chapter 1.3 --- Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) --- p.3 / Chapter 1.3.1 --- Epidemiology --- p.4 / Chapter 1.3.2 --- Causes and risk factors --- p.4 / Chapter 1.3.3 --- Clinical features --- p.6 / Chapter 1.3.4 --- Morphology --- p.6 / Chapter 1.4 --- Classification of BCP-ALL --- p.7 / Chapter 1.4.1 --- Immunophenotyping --- p.7 / Chapter 1.4.2 --- Cytogenetics and molecular genetics --- p.9 / Chapter 1.5 --- Prognostic factors --- p.13 / Chapter 1.6 --- Current treatments of BCP-ALL --- p.15 / Chapter Chapter 2 --- Literature Review --- p.18 / Chapter 2.1 --- Cytogenetics abnormalities in BCP-ALL --- p.18 / Chapter 2.1.1 --- Chromosomal translocation --- p.18 / Chapter 2.1.2 --- Aneuploidy --- p.21 / Chapter 2.2 --- Epigenetic aberrations --- p.21 / Chapter 2.2.1 --- DNA methylation --- p.22 / Chapter 2.2.2 --- Mechanism of DNA Methylation in Transcription Repression --- p.23 / Chapter 2.3 --- DNA Methylation in Normal Haematopoiesis --- p.25 / Chapter 2.4 --- DNA Methylation in Haematological Malignancies --- p.26 / Chapter 2.4.1 --- DNA methylation in ALL --- p.26 / Chapter 2.4.2 --- DNA methylation in BCP-ALL --- p.29 / Chapter 2.5 --- Angiogenesis in pathogenesis of acute leukemias --- p.30 / Chapter 2.6 --- Thrombospondin-1 (TSP-1) --- p.32 / Chapter 2.6.1 --- Structure of TSP-1 --- p.33 / Chapter 2.6.2 --- The role of TSP-1 in tumorigenesis --- p.34 / Chapter 2.6.3 --- TSP-1 mediates the activation of TGFβ --- p.36 / Chapter 2.6.4 --- TSP-1 mediates TGFβ-induced Apoptosis --- p.37 / Chapter 2.6.5 --- Association of TGFβ with normal haematopoiesis and haematological malignancies progression --- p.40 / Chapter 2.6.6 --- TSP-1 Induced Apoptosis via its Receptor CD36 --- p.42 / Chapter 2.6.7 --- THBS1 promoter hypermethylation and its association with tumorigenesis --- p.43 / Chapter 2.6.8 --- Effect of THBS1 aberrant methylation on TGFp --- p.45 / Chapter Chapter 3 --- Rationale of Study --- p.47 / Chapter Chapter 4 --- Materials and Methods --- p.52 / Chapter 4.1 --- Patient sample --- p.52 / Chapter 4.2 --- Cell lines --- p.52 / Chapter 4.3 --- Mononuclear cells isolation --- p.53 / Chapter 4.4 --- THBS1 promoter hypermethylation analysis --- p.54 / Chapter 4.4.1 --- DNA extraction from mononuclear cells and cell lines --- p.54 / Chapter 4.4.2 --- Bisulfite conversion --- p.55 / Chapter 4.4.3 --- Methylation specific PCR (MSP) --- p.55 / Chapter 4.5 --- Quantification of THBS1 mRNA expression --- p.57 / Chapter 4.5.1 --- RNA extraction --- p.57 / Chapter 4.5.2 --- Reverse transcription PCR --- p.58 / Chapter 4.5.3 --- Real-time RT-PCR --- p.58 / Chapter 4.6 --- Determination of plasma TSP-1 level --- p.59 / Chapter 4.7 --- TSP-1 treatment --- p.60 / Chapter 4.8 --- Flow cytometry analysis --- p.60 / Chapter 4.8.1 --- Annexin-V analysis --- p.60 / Chapter 4.8.2 --- Cell fixation --- p.61 / Chapter 4.8.3 --- Analysis of Caspase-3 activation --- p.62 / Chapter 4.8.4 --- "Analysis of TGFβ downstream pathway activation: Phosphorylation of Smad2/3, JNK and p38" --- p.62 / Chapter 4.9 --- Determination ofTGF-β expression --- p.63 / Chapter 4.10 --- Statistical analysis methods --- p.64 / Chapter Chapter 5 --- Results / Chapter 5.1 --- THBS1 methylation statuses in BCP-ALL patients and cell lines --- p.66 / Chapter 5.2 --- Correlation of THBS1 methylation statuses and clinico- pathological features in BCP-ALL patients --- p.68 / Chapter 5.3 --- Association of THBS1 methylation and THBS1 mRNA expression --- p.69 / Chapter 5.4 --- Effect of TSP-1 treatment on apoptosis level of BCP-ALL cells --- p.72 / Chapter 5.4.1 --- Annexin-V assay --- p.72 / Chapter 5.4.2 --- Caspase-3 activation assay --- p.75 / Chapter 5.5 --- THBS1 methylation and activation of secreted TGFβ --- p.78 / Chapter 5.6 --- Effect of TSP-1 treatment on activation of TGFβ --- p.80 / Chapter 5.7 --- The involvement ofTGFβ activation in TSP-1 induced apoptosis in BCP-ALL --- p.82 / Chapter 5.8 --- The association of TGFβ signaling pathway activities with THBS1 methylation --- p.86 / Chapter Chapter 6 --- Discussion --- p.91 / Chapter 6.1 --- THBS-1 promoter hypermethylation in BCP-ALL cell lines and patients: Correlation with expression and clinico-pathological profile --- p.93 / Chapter 6.1.1 --- THBS1 promoter hypermethylation status in childhood BCP-ALL --- p.93 / Chapter 6.1.2 --- THBS1 methylation as prognostic markers --- p.94 / Chapter 6.1.3 --- "Association of THBS1 methylation status, mRNA expression and TSP-1 protein expression in childhood BCP-ALL" --- p.96 / Chapter 6.2 --- Study of the correlation of TSP-1 induced apoptosis with the THBS1 promoter methylation status --- p.99 / Chapter 6.3 --- Elucidation of the molecular mechanisms of TSP-1 induced apoptosis: study of the involvement of TGFβ activation --- p.103 / Chapter 6.3.1 --- Latent TGFβ activation by TSP-1 in BCP-ALL and association with THBS1 methylation status --- p.103 / Chapter 6.3.2 --- TSP-1 induced cell death through activation ofTGFβ --- p.105 / Chapter 6.3.3 --- TSP-1 induced apoptotic signals via TGFβ signaling pathway --- p.107 / Chapter 6.4 --- Limitation of study --- p.113 / Chapter 6.5 --- Future studies --- p.114 / Chapter 6.5.1 --- Continuation study in TSP-1 induced TGFβ-mediated pathways --- p.114 / Chapter 6.5.2 --- Microarray analysis --- p.115 / Chapter 6.6 --- TSP-1 in treatment of childhood BCP-ALL --- p.115 / Chapter Chapter 7 --- Conclusion --- p.117 / Reference --- p.118

Identiferoai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_327263
Date January 2010
ContributorsNg, Ka Yan., Chinese University of Hong Kong Graduate School. Division of Anatomical and Cellular Pathology.
Source SetsThe Chinese University of Hong Kong
LanguageEnglish, Chinese
Detected LanguageEnglish
TypeText, bibliography
Formatprint, xxi, 131 leaves : ill. (chiefly col.) ; 30 cm.
RightsUse of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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