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Epigenetic Mechanisms of Ikaros Mediated Tumor Suppression in B-Cell Acute Lymphoblastic Leukemia
Richman, Alyssa
Richman, Alyssa
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Abstract
Regulation of gene expression is essential for maintaining cell identity, particularly in diseases like B-cell acute lymphoblastic leukemia (B-ALL), where epigenetic profiles can differentiate cancer subtypes and inform prognosis. Therefore, distinguishing cancer-specific epigenetic characteristics can identify important biomarkers as well as potential therapeutic targets. This dissertation investigates the role of the hematopoietic transcription factor Ikaros, encoded by gene IKZF1, as a tumor suppressor in B-ALL. Ikaros is required for B-cell development, and IKZF1 gene deletions are associated with poor prognostic outcomes in B-ALL, yet the mechanisms of its tumor suppression function are not yet fully resolved. In this work, I elucidated epigenetic mechanisms of Ikaros-mediated tumor suppression in B-ALL by exploring its role in gene regulation using a multi-omic approach, which focused on gene regulatory networks, DNA methylation, and histone modifications in patient-derived B-ALL cells with an IKZF1deletion. In the first part of this dissertation, I analyzed gene regulatory networks and transcription factor dynamics directed by Ikaros. I identified key transcription factors that drive a leukemogenic gene program in IKZF1-deleted cells. Notably, I showed an interaction between Ikaros and the ETS-family member ERG, which is critical for B-ALL cell survival. Next, I comprehensively characterized chromatin states by delineating the genome-wide pattern of histone modifications. Ikaros function significantly altered enhancer activity at genes associated with B-cell proliferation and differentiation. Lastly, I interrogated whole genome DNA methylation to reveal a direct role of Ikaros in regulating DNA methylation at genes where methylation level correlated with patient survival. Overall, this dissertation provides insights into the gene regulatory and epigenetic programs modulated by Ikaros, enhancing our understanding of its role in B-ALL tumor suppression. I provide an integrative, multi-scaled approach to uncover underlying biology of disease, identify epigenetic biomarkers, and ultimately identify therapeutic vulnerabilities that could inform future treatments.
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2024-01-01