Novel Biomarkers of Pediatric B-cell Acute Lymphoblastic Leukemia

    Research output: Book/ReportDoctoral thesisCollection of Articles

    Abstract

    B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. It is characterized by the fast proliferation of clonal white blood cells in the bone marrow and blood. Occasionally, B-ALL may infiltrate lymph nodes and other sites outside of bone marrow, such as the CNS. Although the prognosis has improved dramatically during the past decades through intensification of the treatment and monitoring of response to treatments, relapse of the disease is still a ma1or cause of morbidity and mortality. This prevalent hardship forces the continuous re-evaluation of disease classification and investigation for novel treatments.

    The pathogenesis of B-ALL includes the aberrant expression of different transcription factors that lead to uncontrolled proliferation and derailed migration of leukemic populations. This dissertation focused on two transcription factors, namely neurodevelopmental and mantle cell lymphoma-associated transcription factor SOX11 and the germinal center-originated lymphoma-associated proto- oncogene BCL6, along with the oncofetal post-transcriptional modifier protein IGF2BP3. We utilized pre-existing gene expression datasets, collected a population- based immunohistochemistry sample cohort, and correlated the findings to treatment response and patient survival.

    We found BCL6 was associated with the TCF3-PBX1 subtype and several novel subtypes, such as, MEF2D and components of the pre-BCR signaling pathway. At mRNA level, higher BCL6 levels indicated better prognosis. SOX11 was expressed particularly in ETV6-RUNX1 and TCF3-PBX1 subtypes of B-ALL, and high expression of SOX11 protein was associated with a favorable outcome. Low level of SOX11 promoter methylation was likely behind the high expression and high methylation levels could be overcome by treatment with demethylating agent decitabine. Finally, IGF2BP3 was discovered to be widely expressed in B-ALL at protein and mRNA levels and associated with a proliferative cell phenotype. High levels of IGFBP3 mRNA were associated with better treatment response in high-risk B-ALL cases.

    In summary, we found several potential novel biomarkers for B-ALL. Although the results suggest prognostic utility in patient care, they require further validation in prospective cohorts and with current treatment protocols before application in clinics.
    Original languageEnglish
    Place of PublicationTampere
    ISBN (Electronic)978-952-03-2468-1
    Publication statusPublished - 2022
    Publication typeG5 Doctoral dissertation (articles)

    Publication series

    NameTampere University Dissertations - Tampereen yliopiston väitöskirjat
    Volume629
    ISSN (Print)2489-9860
    ISSN (Electronic)2490-0028

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