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UBC Theses and Dissertations

Gene expression and mutation profiles define novel subclasses of cytogenetically normal acute myeloid leukemia Pilsworth, Jessica


Acute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by the accumulation of acquired somatic genetic abnormalities in hematopoietic progenitor cells. Recurrent chromosomal rearrangements are well-established diagnostic and prognostic markers. However, approximately 50% of AML cases have normal cytogenetics and have variable responses to conventional chemotherapy. Molecular markers have been begun to subdivide cytogenetically normal AML (CN-AML) and have been shown to predict clinical outcome. Despite these achievements, current classification schemes are not completely accurate and improved risk stratification is required. My overall objective was to identify specific gene expression and mutation signatures to define novel subclasses of CN-AML. I hypothesized that CN-AML would be separated into at least two or more subgroups. Gene expression and mutational profiles were established using RNA-Sequencing, clustering, de novo transcriptome assembly, and variant detection. I found the CN-AML could be separated into three groups, two of which had statistically significant survival differences (Kaplan-Meier analysis, log-rank test, p=9.75x10-³). Variant analysis revealed nine fusions that are not detectable via cytogenetic analysis and differential expression analysis identified a set of discriminatory genes to classify each subgroup. These findings contribute to the current understanding of the genetic complexity of AML and highlight gene fusion candidates for follow-up functional analyses.

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