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Applications of transcriptome profiling for clinical assessment of acute myeloid leukemia

University of British Columbia

Acute myeloid leukemia (AML) is a blood-based cancer with dismal outcomes and limited therapeutic options. Clinical applications of next-generation sequencing (NGS) methods offer a potential avenue for improved diagnosis, stratification, and therapy selection for AML. In particular, RNA sequencing has the potential to provide a wealth of genome-wide information of potential clinical relevance. However, the analytic validity of RNA-Seq as a clinical assay for AML has not been established. In this thesis, I first compare RNA-Seq to whole-exome sequencing (WES) and whole-genome sequencing (WGS) approaches, and demonstrate that RNA-Seq offers the most broad benefits for clinical assessment of AML at diagnosis. To determine whether RNA-Seq information could be used to improve upon the current clinical stratification model for AMLs, I develop a novel gene expression signature. Together with demonstrating improved stratification performance, I find that a subset of high-risk AML cases are characterized by dysregulated integrin signaling, and are potentially amenable to treatment with existing inhibitors. To further characterize the dysregulated transciptome in AML, I analyze miRNA sequence data from the same patient cohorts, observing that the dysregulation of key miRNAs may be involved in up-regulation of integrin signaling. Taken together, the results presented in this thesis offer a path towards improved clinical diagnostics in AML, together with a deeper understanding of transcriptomic dysregulation at both the mRNA and miRNA levels.

Text

2022-08-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/75517

Experimental Medicine

University of British Columbia

UBCV

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