Gene transcription is fundamental in establishing and maintaining cell identity and function. All normal cells are encoded with the same DNA, so transcription is essential for regulating many biological processes, including blood cell formation. Dysregulation of the complex transcriptional mechanisms governing blood cell formation can result in the development of hematologic malignancies, including acute myeloid leukemia (AML). AML is an aggressive blood cancer characterized by the rapid outgrowth of immature blood cells. Despite advances in treatment, AML remains an often fatal disease with a 5-year survival rate of less than 30%. This dissertation aims to uncover mechanisms of transcriptional dysregulation in AML, nominating novel molecular targets that can be used to design more effective treatment strategies.