Exploring mechanisms of T-cell acute lymphoblastic leukemia pathogenesis through molecular characterization of normal T-cell development
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Wong, Alana Rachel
issued: 2022-09-09T22:49:42Z
issued: 2022
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: T-cell development and lineage commitment are temporally protracted processes in which the interplay between transcription factors and epigenetic modulators orchestrate the sequential exclusion of alternative fates and acquisition of specialized T-cell functions. Alterations during this process can lead to diseases such as T-cell acute lymphoblastic leukemia (T-ALL). While much work has focused on the transcription factors which drive normal development and T-ALL, the underlying epigenetic constraints remain poorly characterized. The central objective of the work presented in this thesis is to gain a greater understanding of the molecular events during early human T-cell differentiation to allow for dissection of particular genetic events that may occur in T-ALL. This was addressed through a detailed transcriptomic characterization of T-ALL within the framework of normal development, and through genetic perturbation and functional characterization of in vitro-differentiating T-cell subsets. The findings revealed; 1) an improved classification of T-ALL which better captures the developmental context in which specific transcription factors operate and which improves upon the identification of clinically relevant disease subgroups, and 2) novel insights into a role of DNMT3A in restricting lineage-specific signal responses in T-cell development and T-ALL. The results of functional assays revealed that DNMT3A loss increased signaling plasticity in T-lineage-restricted populations, as measured by response to cytokines typically affiliated with the myeloid lineage. This was enriched within a population of lineage-restricted T-cells expressing the G-, M-, and/or GM-CSF receptors, and was associated with proliferation and acquisition of a myeloid-like phenotype. Further investigation of the expression of these receptors revealed their prevalence in human T-ALL cell lines and post-natal thymus, thus indicating the biological relevance of CSF receptor expression in human tiss…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/82688
note: EXPLORING MECHANISMS OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA PATHOGENESIS THROUGH MOLECULAR CHARACTERIZATION OF NORMAL T-CELL DEVELOPMENT by Alana Rachel Wong B.Sc. (Honours and Co-op), University of Victoria, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Interdisciplinary Oncology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) September 2022 © Alana Rachel Wong, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Exploring mechanisms of T-cell acute lymphoblastic leukemia pathogenesis through molecular characterization of normal T-cell development submitted by Alana Rachel Wong in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Interdisciplinary Oncology Examining Committee: Andrew Weng, Professor, Pathology & Laboratory Medicine, UBC Supervisor Gregg Morin, Professor, Medical Genetics, UBC Supervisory Committee Member Ninan Abraham, Professor, Department of Microbiology and Immunology, Department of Zoology, UBC University Examiner Fumio Takei, Professor, Pathology & Laboratory Medicine, UBC University Examiner Additional Supervisory Committee Members: Christian Steidl, Professor, Pathology & Laboratory Medicine, UBC Supervisory Committee Member iii Abstract T-cell development and lineage commitment are temporally protracted processes in which the interplay between transcription factors and epigenetic modulators orchestrate the sequential exclusion of alternative fates and acquisition of specialized T-cell functions. Alterations during this process can lead to diseases such as T-cell acute lymphoblastic leukemia (T-ALL). While much work has focused on the transcription factors which drive normal development and T-ALL, the underlying epigenetic constraints remain poorly characterized. The central object…
has type: Thesis/Dissertation
date issued: 2022-11
is shown at: 10.14288/1.0419315
language: eng
degree discipline: Interdisciplinary Oncology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Weng, Andrew
type: Text
identifier URI: http://hdl.handle.net/2429/82688