Acute myeloid leukemia (AML) is the most aggressive form of hematological malignancies. Despite advances in treating AML, development of resistance to nucleoside analog therapy remains one of the major obstacles in AML treatment. Various factors, including SNPs in genes, epigenetics, etc. play a role in mediating variability in response to nucleoside analog therapy. Recent studies have shown that microRNAs can also serve as regulators of gene expression that can contribute to variability in response to therapeutic agents. Thus the main objective of the thesis was to determine the role of microRNAs as predictors of variability in nucleoside analog response. To our knowledge no studies have been reported that identify microRNAs as predictors of response to cytarabine therapy in AML patients. In chapter II we used a translational approach of conducting in vitro and clinical study to identify microRNAs that were predictive of overall survival in AML patients. Our study conclusively identified that miR107-Myb, miR-378-granzyme B and miR10a-MAP4K4 as miRNA-mRNA pairs that can be used as predictors of overall survival in AML patients. Additionally, we also showed that the miRNAs mechanistically regulate the expression of these mRNAs by binding to the 3’- untranslated region of these mRNAs. miRNAs can also cause variability in response to cytarabine therapy by regulating the expression of the genes involved in disposition of cytarabine. In chapter III we identified that miR-24 and miR-34a as regulator of DCTD (an enzyme involved in inactivation of cytarabine) and DCK (activating enzyme), respectively. These miRNAs along with other miRNAs can be used as part of biomarker signature that can be used to predict the overall survival in AML patients. In chapter IV, we determined the impact of cytarabine treatment on in vivo cytarabine-induced changes in leukemia cell transcriptome and miRNA expression, to evaluate their impact on clinical outcome. In the first part of this chapter, we identified key genes (such as tumor suppressors DKK3, TRIM33, PBRM1, an oncogene SET, cytidine-deaminase family members APOBEC2 and APOBEC3G) influenced by cytarabine infusion that were also predictive of response. In the second part of this chapter, using data from clinical studies, we identified several miRNAs that were altered by cytarabine treatment. The changes in the expression of these miRNAs resulted in alteration in gene expression that correlated with the overall survival in AML patients. Additionally, using cell lines we were able to identify various miRNA – mRNAs that were altered by drug treatment, indicating that the therapy itself can influence the predictive ability of miRNAs as biomarkers. Significant data has been published on cytarabine as it is the standard of care in AML patients, however, there is limited knowledge about newer nucleoside analogs such as clofarabine. In chapter V, using in vitro methods, we identified several microRNAs, such as miR-16, miR-515 cluster, etc., that can be used as predictors of response for clofarabine therapy. Our data clearly suggests that there are several distinct microRNAs that can be used as predictors of response to clofarabine therapy in AML patients. We propose doing a clinical study to evaluate the clinical utility of these miRNAs as predictors of response. In summary, using a translational approach, we were able to identify miRNAs and several miRNA-mRNA pairs that can be used as biomarkers of response to cytarabine therapy. Additionally, we also identified that drug therapy itself can influence the outcome in AML patients. These findings are clinically important as they will help provide a new strategy to optimize dosing of nucleoside analogs in AML patients which in turn would lead to better overall survival while reducing the side effects.
University of Minnesota Ph.D. dissertation. December 2015. Major: Experimental & Clinical Pharmacology. Advisor: Jatinder Lamba. 1 computer file (PDF); xiv, 250 pages.
MicroRNAs As Predictors of Nucleoside Analog Sensitivity in Acute Myeloid Leukemia.
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