Date of Award

12-2013

Level of Access

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Pradeep Sathyanarayana

Second Committee Member

Robert Friesel

Third Committee Member

Lucy Liaw

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease marked by a highly variable clinical course and response to therapy. The average age of individuals diagnosed with AML is approximately 69 years old. Due to age of the patient and how quickly the disease progresses, many are unable to receive therapy, leading to death between 4 and 12 weeks after diagnosis. More effective and less cytotoxic treatments are crucial for those diagnosed with AML. Therefore my work has been focused on understanding genetic pathways altered within AML to develop new-targeted therapies. Specifically, I have been studying microRNAs (miR), which regulate proteins by degrading the protein messages prior to them becoming functional. MicroRNA-125a (miR-125a) previously was identified as being decreased in cytogenetically normal AML. I have identified that miR-125a is decreased in many subtypes of AML. Correlation of miR-125a to a specific AML subtype was difficult due to the range of molecular and cytogenetic abnormalities. By ectopically expressing miR-125a, leukemic blasts have decreased cell proliferation, cell cycle progression, and enhanced apoptosis. Through profiling analysis, I have identified Trib2 as a new target of miR-125a though its function has not been characterized. Secondly, I have discovered that the ErbB pathway, a growth promoting pathway, currently known to cause breast and gastric cancer, is enhanced in AML when miR-125a is decreased. As a result of these studies, I have identified a potential new therapeutic, Mubritinib. Currently Mubritinib is being utilized in cancer, such as breast cancer but not yet in blood disorders. From this discovery an additional cancer could be treated with current ErbB inhibitors as a new therapeutic application.

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