Date of this Version
Caplan, M. 2020, Identifying protein expression changes in acute myeloid leukemia. Honors Undergraduate Thesis. University of Nebraska-Lincoln.
Acute myeloid leukemia (AML) is a devastating cancer affecting the hematopoietic system. It is characterized by infiltration of abnormal proliferating immature myeloid cells originating in the bone marrow. Although this disease represents only 35% of diagnosed leukemias, it accounts for nearly 50% of leukemia-related deaths, making it the leading cause of leukemia-related mortality. Disease initiation often occurs through common recurrent genetic aberrations resulting in the formation of oncogenic fusion proteins. Two common mutations include mixed lineage leukemia (MLL) rearrangements and an inversion of chromosome 16, known as Inv(16). Although many of these AML initiating mutations have been identified, the downstream effects leading to disease progression are still largely unknown. Previous research has relied on RNA sequencing and microarray techniques to study the downstream effects, providing data at the transcriptional level. While these studies have proven efficacious, they fail to capture the changes that occur at the proteomic level. To interrogate the effect of protein expression alterations in AML, we performed a quantitative mass spectrometry (MS) analysis using mouse models to compare three tumor types (Inv(16), MLL-AF9, and MLL-ENL) to untransformed cells from the tumor-initiating population. In parallel, we performed RNA sequencing for the same populations. With these combined results, we identified 61 proteins whose expression was upregulated in AML tumors, but strikingly, were unaltered at the transcriptional level. These proteins are shown to be associated with mitochondrial function as well as RNA processing. In addition, analysis of patient expression data sets in adult and pediatric AML reveal that a number of the proteins differentially expressed have no significant RNA expression alterations. These studies identify a set of proteins that have not previously been associated with leukemia, and may ultimately serve as potential targets for therapeutic manipulation to hinder AML progression and elucidate molecular mechanisms driving this disease.