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dc.contributor.authorMoore, Alison
dc.contributor.otherQueen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.))en
dc.date.accessioned2019-06-26T20:43:35Z
dc.date.available2019-06-26T20:43:35Z
dc.identifier.urihttp://hdl.handle.net/1974/26335
dc.description.abstractTreatment of acute lymphoblastic leukemia (ALL) has become quite effective over the last two decades. However, further progress is limited by a lack of understanding of the biological processes that drive this disease. This understanding will be crucial for developing effective targeted therapies. The oncogenic transcription factor TCF3-PBX1 is expressed in 5% of ALL cases consequent to a somatic chromosomal translocation between chromosomes 1 and 19. It is broadly accepted that TCF3-PBX1 acts as a transcriptional activator resulting in dysregulated proliferation, survival and/or differentiation of hematopoietic cells. Studies have implicated the histone acetyltransferase p300 as an important player in mediating these transcriptional effects. However, the particular binding sites of TCF3-PBX1 and the genes affected have not been identified. We hypothesized that TCF3-PBX1 binds to B-lymphopoietic cis-regulatory regions, such as enhancers and promoters, via the PBX1 homeodomain and affects gene transcription by recruiting p300 in a manner that leads to leukemogenesis. Through the use of chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq), this project identified over 3500 genomic regions where TCF3-PBX1 binds in a t(1;19)-bearing, ALL-derived cell line that expresses endogenous TCF3-PBX1. Most binding sites have characteristics associated with cis-regulatory elements, such as particular histone modifications, and are commonly occupied by B-lymphopoietic transcription factors and PBX family members. TCF3-PBX1 additionally recruits p300 to novel sites, which plays a role in increasing the expression of nearby genes. One hundred and sixty-three genes had nearby TCF3-PBX1 binding sites and were differentially expressed (determined using RNA-sequencing) upon short-hairpin RNA-mediated knockdown of TCF3-PBX1 in two cell lines, suggesting that they are direct transcriptional targets of TCF3-PBX1. Fifty-eight of these genes were additionally found to be differentially expressed between primary, patient-derived ALL samples that likely do, versus do not, harbor the t(1;19) translocation. Together, these results support our hypothesis described above and address the need to identify the transcriptional targets of the TCF3-PBX1 fusion oncoprotein. These target genes and their associated cellular pathways will inform future studies to elucidate the molecular mechanisms by which TCF3-PBX1 disturbs lymphoid development in ALL and will contribute to the eventual development of novel treatments that target these mechanisms.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectchromatin immunoprecipitationen_US
dc.subjectacute lymphoblastic leukemiaen_US
dc.subjectTCF3-PBX1en_US
dc.subjectgenome-wideen_US
dc.subjecttranscriptional regulationen_US
dc.titleExploring the Genomic Binding Landscape of the Oncogenic Transcription Factor TCF3-PBX1 in Acute Lymphoblastic Leukemiaen_US
dc.typethesisen
dc.description.degreeMaster of Scienceen_US
dc.contributor.supervisorLeBrun, David
dc.contributor.departmentPathology and Molecular Medicineen_US
dc.embargo.termsWe are looking to publish this competitive work shortly (within the next year). Please restrict for 5 years.en_US
dc.embargo.liftdate2024-06-26T19:48:41Z


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