Please use this identifier to cite or link to this item: https://scholarbank.nus.edu.sg/handle/10635/226241
Title: REQUIREMENT OF TP73 IN CANCER CELL MAINTENANCE AND GENETIC ALTERATIONS EVOLVING FROM ITS INTRAGENIC SUPER-ENHANCER
Authors: ONG ZU LIN JOLYNN
ORCID iD:   orcid.org/0000-0001-8049-1791
Keywords: super-enhancer, genomic instability, clonal evolution
Issue Date: 20-Jan-2022
Citation: ONG 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.
Abstract: Active 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.
URI: https://scholarbank.nus.edu.sg/handle/10635/226241
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