Open Collections

Im, Junbum

University of British Columbia

Acute myeloid leukemia (AML) is a deadly hematological malignancy that emerges from impaired differentiation and aberrant proliferation of immature myeloid blasts in the bone marrow. Around 11% of AML patients can express the protein ecotropic viral integration site 1 (EVI1), a stem cell regulator that leads to decreased survival rates in AML. Although drug resistance triggered by EVI1 remains incompletely understood, recent research indicates that adverse risk AML is frequently characterized by diminished mitochondrial priming, a state associated with reduced apoptosis. Mitochondrial priming controls intrinsic apoptosis via Cytochrome C (CYC) release, initiated by the proteins BAK and BAX which triggers the apoptotic cascade and the downregulation of BAK/BAX leads to strong treatment resistance. Restoring mitochondrial priming shows therapeutic potential for EVI1+ AML, but mechanisms regulating this state have not been elucidated. Therefore, this thesis sought to uncover and investigate a target to increase mitochondrial priming and treatment response in EVI1+ AML. The work here shows that EVI1+ AML strongly correlated with O-GlcNAc transferase (OGT), a post-translational modifier associated in regulating various cellular processes, including stress response and survival. Inhibiting OGT increased expression of both BAK and BAX, indicating an increase in mitochondrial priming. BH3 profiling on EVI1+ AML cell lines and patient samples was conducted and showed that OGT inhibition increased CYC release upon treatment with both BID and BIM peptides. Proteomics analysis also revealed that OGT inhibition negatively enriched stress granule assembly and high G3BP1 levels were present in EVI1+ AML. These G3BP1 aggregates were associated with BAK and BAX mRNA and diminished with OGT inhibition. Subsequently, the increased mitochondrial priming improved treatment response in EVI1+ AML cell lines and patient samples. In a combinatorial drug screen, the OGT inhibitor OSMI-4b synergized strongly with Venetoclax and other AML treatments in inducing caspase3/7 cleavage and cell death. Therefore, EVI1+ AML is associated with high OGT levels and activity to increase its survival through BAK1 and BAX suppression. Mitochondrial priming and treatment response can be restored by inhibiting OGT, establishing a preclinical rationale for OGT inhibition as a novel therapeutic strategy for this disease.

Text

2025-04-17

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90684

Interdisciplinary Oncology

University of British Columbia

UBCV

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