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Characterization of programmed death ligands in B-cell non-Hodgkin lymphomas

University of British Columbia

Non-Hodgkin lymphomas constitute a conglomerate of malignancies that originate from a population of white blood cells termed lymphocytes. Lymphoid cancers are a significant health burden in Canada, with over 9,200 new diagnoses in 2018. Of those newly diagnosed, roughly 40% will die within five years. Studying a subpopulation of aggressive B-cell derived non-Hodgkin lymphomas with both high-throughput sequencing and conventional research techniques, we identified recurrent, somatic aberrations in two genes that are contributors to lymphoma pathogenesis: programmed death ligands 1 (CD274) and 2 (PDCD1LG2). In healthy individuals, programmed death ligands are central to maintaining peripheral tolerance and preventing autoimmune disease. However, we establish that malignant B-cells hijack this axis to suppress the antitumor immune response.Within this dissertation, we report on the frequency of programmed death ligand structural genomic rearrangements in seven different B-cell lymphoma entities and demonstrate the effects of structural genomic rearrangements on gene expression. Additionally, we evaluate ectopic cytokine stimulation, copy number variations, DNA methylation, and micro RNA regulation as additional mechanisms of deregulating programmed death ligand expression. Using novel, capture-based high-throughput techniques, we characterize, at base-pair resolution, the subtypes, cluster locations, and partners of programmed death ligand structural genomic rearrangements. We go on to demonstrate the effects of protein expression and characterize the functional impairment resulting from deregulated programmed death ligand binding in both B and T-cell populations using retroviral cell line models. Finally, in evaluating flanking breakpoint sequences of programmed death ligand structural genomic rearrangements, we propose the molecular mechanisms involved in producing these aberrations. Taken together, our work informs on relevant components of B-cell non-Hodgkin lymphoma pathogenesis and substantiates the effectiveness of molecularly precise therapies targeting the programmed death ligand axis, as they become mainstays of lymphoma treatment.

Text

2022-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74791

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/