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Lee, Kiera Jane

University of British Columbia

Synovial sarcoma (SS) is a soft-tissue malignancy that mainly impacts adolescents and young adults and has limited response to existing systemic treatments. SS is characterized by a chromosomal translocation t(X;18), resulting in the oncogenic protein SS18::SSX, beyond which SS is extremely mutationally quiet. SS is an epigenetically driven disease with oncogenesis occurring through BRG/BRM Associated Factors (BAF) complex and polycomb repressive complex (PRC) dysregulation. SS18::SSX is incorporated into the ATP-dependant chromatin remodeling complexes, cBAF and GBAF in place of canonical SS18, causing BAF complex retargeting. In my research, I leverage access to multi-omic datasets of 52 SS tumor samples. My analysis confirms SS enhancer subgroups with distinct H3K27ac profiles, and a shared SS promoter landscape that may provide a therapeutic vulnerability. The enhancer subgroups are characterized by distinct patterns of H3K27ac peak proximity to gene transcription start sites and by the motifs they are associated with. The promoter landscapes show striking expansion of H3K4me3 and hypomethylation, across samples. I hypothesize that (1) The H3K27ac enhancer landscape reflects the SS18::SSX levels and can be shifted through SS18::SSX depletion. (2) The H3K4me3 expansion and (3) promoter hypomethylation are targetable therapeutic vulnerabilities. I test these hypotheses through the following aims: 1) analysis of the H3K27ac epigenetic patterns across the tumour cohort and correlation to clinical data 2) selective drug testing that targets the expansion of H3K4me3 and hypomethylation at promoters. I find that the H3K27ac enhancer landscape is not independently controlled by the amount of SS18::SSX within the tumour cells and instead may represent a cell-of-origin difference between the tumour subgroups. Second, I demonstrate that the H3K4me3 expansion at SS promoters is a therapeutic vulnerability that can be targeted by inhibiting the H3K4me3 methyltransferase complex subunit, WDR5. Finally, I determine that targeting the hypomethylation of SS promoters with the oncometabolite 2-hydroxyglutarate does not show a therapeutic potential in SS cell lines. My work contributes to our understanding of the enhancer landscape in SS, and supports WDR5 inhibition as a future therapeutic target in SS.

Text

2025-06-25

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/91442

Interdisciplinary Oncology

University of British Columbia

UBCV

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