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UBC Theses and Dissertations

Exploring mechanisms of T-cell acute lymphoblastic leukemia pathogenesis through molecular characterization of normal T-cell development Wong, Alana Rachel


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 tissues. Stimulation of the CSF receptor-expressing population by adding cognate ligands revealed a proliferative advantage in T-ALL cells, but only upon DNMT3A loss. These results suggest that DNMT3A may act to preclude response to alternative-lineage factors in T-cells, and furthermore point to a mechanism of selective advantage in a subset of T-ALL.

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