Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/226241
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dc.titleREQUIREMENT OF TP73 IN CANCER CELL MAINTENANCE AND GENETIC ALTERATIONS EVOLVING FROM ITS INTRAGENIC SUPER-ENHANCER
dc.contributor.authorONG ZU LIN JOLYNN
dc.date.accessioned2022-05-31T18:00:45Z
dc.date.available2022-05-31T18:00:45Z
dc.date.issued2022-01-20
dc.identifier.citationONG ZU LIN JOLYNN (2022-01-20). REQUIREMENT OF TP73 IN CANCER CELL MAINTENANCE AND GENETIC ALTERATIONS EVOLVING FROM ITS INTRAGENIC SUPER-ENHANCER. ScholarBank@NUS Repository.
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/226241
dc.description.abstractActive enhancer elements are accessible chromatin regions that are prone to DNA double- strand breaks. In this study, I tested the hypothesis that structural variants (SVs) arising from intragenic super-enhancers may lead to functional alterations in the affected gene and contribute to cancer evolution. Using an integrative approach for adult T-cell leukemia/lymphoma (ATL), a genetically complex hematological malignancy, we selected genes that harbor recurrent SVs within their super-enhancers. This approach highlighted TP73, which is highly activated under the control of a super-enhancer and is required for ATL cell maintenance in vitro and in vivo via the regulation of cell proliferation and DNA damage response pathways. Recurrent deletions of TP73 exons 2- 3 were frequently observed in primary ATL cases that harbored the super-enhancer, while induction of this deletion in cell lines further increased proliferation and mutational burden, thereby conferring additional clonal advantage. Caveolin-1 expression was associated with the genetic status of TP73, serving as a surrogate marker. Collectively, this study provides several novel insights into leukemia biology. It is the first showing the potential association between super-enhancers and structural variants while highlighting the uncharacterized roles of TP73 in ATL cell maintenance and the evolution of its genetic alterations. Lastly, I also propose a previously undescribed relationship between CAV1 and TP73 genetic status which has future clinical implications given that CAV1 is a secreted molecule that could be used as a prognostic serum biomarker.
dc.language.isoen
dc.subjectsuper-enhancer, genomic instability, clonal evolution
dc.typeThesis
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.supervisorTakaomi Sanda
dc.description.degreePh.D
dc.description.degreeconferredDOCTOR OF PHILOSOPHY (CSI)
dc.identifier.orcid0000-0001-8049-1791
Appears in Collections:Ph.D Theses (Restricted)

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