The molecular characterisation of childhood acute lymphoblastic leukaemia: gene expression profiles to elucidate leukaemogenesis

Joanne Boag

    Research output: ThesisDoctoral Thesis

    194 Downloads (Pure)

    Abstract

    [Truncated abstract] Acute lymphoblastic leukaemia (ALL) is the most common form of cancer that affects children and the leading cause of child cancer-related death. There have been dramatic improvements in the 5-year event free survival (EFS) for childhood ALL in recent years, with EFS reaching 75-90% for some forms of the disease. Despite this success, treatment for the disease is aggressive with numerous long and short-term side effects. Many cases of ALL are characterised by chromosomal defects including translocations, variations in chromosome number and the deletion of the tumour suppressor genes. Although these gross chromosomal changes have been extensively studied in childhood ALL, the cascade of altered gene expression that results from these changes has not. Further improvements in survival and the quality of life of survivors relies on a better understanding of the underlying biology of ALL. The primary aim of this study was to determine the gene expression profile of pre-B ALL specimens and normal, or non-malignant, control cells using microarrays in order to further examine the underlying biology of childhood ALL. ... Analysis of the ALL profile with two normal haematopoietic populations demonstrated that ALL specimens have a profile similar to that of CD34+ cells. Specifically, specimens of the MLL subtype had a profile that uniformly resembled that of CD34+ cells. Other subgroups contained specimens with profiles that ranged in similarity to that of CD34+ cells, however, the gene expression profile of all ALL specimens analysed more closely resembled the CD34+ cells than the more differentiated CD19+IgM- cells. This study identified exceptionally high expression of connective tissue growth factor (CTGF/CCN2) in ALL specimens compared to control cells. CTGF expression was v restricted to B-lineage ALL specimens, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies by Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. The study presented here provides insight into the biology of ALL including the observation that ALL cells have an immature gene expression profile similar to that of CD34+ cells and the possible existence of an autocrine loop involving CTGF. The findings may also have clinical application in the future treatment of ALL, such as the use of metabolic inhibitors or the blocking of CTGF expression. This study provides an important insight into many aspects of ALL disease biology and may offer potential new therapeutic targets for the treatment of ALL.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2006

    Fingerprint

    Precursor Cell Lymphoblastic Leukemia-Lymphoma
    Transcriptome
    Disease-Free Survival
    Connective Tissue Growth Factor
    Chromosome Deletion
    Conditioned Culture Medium
    Tumor Suppressor Genes

    Cite this

    @phdthesis{d984a972ab7549f8bfdb8f4e1eaa29fa,
    title = "The molecular characterisation of childhood acute lymphoblastic leukaemia: gene expression profiles to elucidate leukaemogenesis",
    abstract = "[Truncated abstract] Acute lymphoblastic leukaemia (ALL) is the most common form of cancer that affects children and the leading cause of child cancer-related death. There have been dramatic improvements in the 5-year event free survival (EFS) for childhood ALL in recent years, with EFS reaching 75-90{\%} for some forms of the disease. Despite this success, treatment for the disease is aggressive with numerous long and short-term side effects. Many cases of ALL are characterised by chromosomal defects including translocations, variations in chromosome number and the deletion of the tumour suppressor genes. Although these gross chromosomal changes have been extensively studied in childhood ALL, the cascade of altered gene expression that results from these changes has not. Further improvements in survival and the quality of life of survivors relies on a better understanding of the underlying biology of ALL. The primary aim of this study was to determine the gene expression profile of pre-B ALL specimens and normal, or non-malignant, control cells using microarrays in order to further examine the underlying biology of childhood ALL. ... Analysis of the ALL profile with two normal haematopoietic populations demonstrated that ALL specimens have a profile similar to that of CD34+ cells. Specifically, specimens of the MLL subtype had a profile that uniformly resembled that of CD34+ cells. Other subgroups contained specimens with profiles that ranged in similarity to that of CD34+ cells, however, the gene expression profile of all ALL specimens analysed more closely resembled the CD34+ cells than the more differentiated CD19+IgM- cells. This study identified exceptionally high expression of connective tissue growth factor (CTGF/CCN2) in ALL specimens compared to control cells. CTGF expression was v restricted to B-lineage ALL specimens, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies by Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. The study presented here provides insight into the biology of ALL including the observation that ALL cells have an immature gene expression profile similar to that of CD34+ cells and the possible existence of an autocrine loop involving CTGF. The findings may also have clinical application in the future treatment of ALL, such as the use of metabolic inhibitors or the blocking of CTGF expression. This study provides an important insight into many aspects of ALL disease biology and may offer potential new therapeutic targets for the treatment of ALL.",
    keywords = "Acute leukemia in children, Genetic aspects, Leukemia in children, Lymphoblastic leukemia in children, Paediatric, Gene expression, Leukaemia",
    author = "Joanne Boag",
    year = "2006",
    language = "English",

    }

    TY - THES

    T1 - The molecular characterisation of childhood acute lymphoblastic leukaemia: gene expression profiles to elucidate leukaemogenesis

    AU - Boag, Joanne

    PY - 2006

    Y1 - 2006

    N2 - [Truncated abstract] Acute lymphoblastic leukaemia (ALL) is the most common form of cancer that affects children and the leading cause of child cancer-related death. There have been dramatic improvements in the 5-year event free survival (EFS) for childhood ALL in recent years, with EFS reaching 75-90% for some forms of the disease. Despite this success, treatment for the disease is aggressive with numerous long and short-term side effects. Many cases of ALL are characterised by chromosomal defects including translocations, variations in chromosome number and the deletion of the tumour suppressor genes. Although these gross chromosomal changes have been extensively studied in childhood ALL, the cascade of altered gene expression that results from these changes has not. Further improvements in survival and the quality of life of survivors relies on a better understanding of the underlying biology of ALL. The primary aim of this study was to determine the gene expression profile of pre-B ALL specimens and normal, or non-malignant, control cells using microarrays in order to further examine the underlying biology of childhood ALL. ... Analysis of the ALL profile with two normal haematopoietic populations demonstrated that ALL specimens have a profile similar to that of CD34+ cells. Specifically, specimens of the MLL subtype had a profile that uniformly resembled that of CD34+ cells. Other subgroups contained specimens with profiles that ranged in similarity to that of CD34+ cells, however, the gene expression profile of all ALL specimens analysed more closely resembled the CD34+ cells than the more differentiated CD19+IgM- cells. This study identified exceptionally high expression of connective tissue growth factor (CTGF/CCN2) in ALL specimens compared to control cells. CTGF expression was v restricted to B-lineage ALL specimens, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies by Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. The study presented here provides insight into the biology of ALL including the observation that ALL cells have an immature gene expression profile similar to that of CD34+ cells and the possible existence of an autocrine loop involving CTGF. The findings may also have clinical application in the future treatment of ALL, such as the use of metabolic inhibitors or the blocking of CTGF expression. This study provides an important insight into many aspects of ALL disease biology and may offer potential new therapeutic targets for the treatment of ALL.

    AB - [Truncated abstract] Acute lymphoblastic leukaemia (ALL) is the most common form of cancer that affects children and the leading cause of child cancer-related death. There have been dramatic improvements in the 5-year event free survival (EFS) for childhood ALL in recent years, with EFS reaching 75-90% for some forms of the disease. Despite this success, treatment for the disease is aggressive with numerous long and short-term side effects. Many cases of ALL are characterised by chromosomal defects including translocations, variations in chromosome number and the deletion of the tumour suppressor genes. Although these gross chromosomal changes have been extensively studied in childhood ALL, the cascade of altered gene expression that results from these changes has not. Further improvements in survival and the quality of life of survivors relies on a better understanding of the underlying biology of ALL. The primary aim of this study was to determine the gene expression profile of pre-B ALL specimens and normal, or non-malignant, control cells using microarrays in order to further examine the underlying biology of childhood ALL. ... Analysis of the ALL profile with two normal haematopoietic populations demonstrated that ALL specimens have a profile similar to that of CD34+ cells. Specifically, specimens of the MLL subtype had a profile that uniformly resembled that of CD34+ cells. Other subgroups contained specimens with profiles that ranged in similarity to that of CD34+ cells, however, the gene expression profile of all ALL specimens analysed more closely resembled the CD34+ cells than the more differentiated CD19+IgM- cells. This study identified exceptionally high expression of connective tissue growth factor (CTGF/CCN2) in ALL specimens compared to control cells. CTGF expression was v restricted to B-lineage ALL specimens, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies by Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. The study presented here provides insight into the biology of ALL including the observation that ALL cells have an immature gene expression profile similar to that of CD34+ cells and the possible existence of an autocrine loop involving CTGF. The findings may also have clinical application in the future treatment of ALL, such as the use of metabolic inhibitors or the blocking of CTGF expression. This study provides an important insight into many aspects of ALL disease biology and may offer potential new therapeutic targets for the treatment of ALL.

    KW - Acute leukemia in children

    KW - Genetic aspects

    KW - Leukemia in children

    KW - Lymphoblastic leukemia in children

    KW - Paediatric

    KW - Gene expression

    KW - Leukaemia

    M3 - Doctoral Thesis

    ER -