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MicroRNAs in myeloid leukemia development and resistance to chemotherapy

Ryan O'Connell

Ryan O'Connell

PhD

The University of Utah

Project Term: July 1, 2017 - June 30, 2022

My lab studies a novel class of molecules, called microRNAs, which are altered in blood disorders such as acute myeloid leukemia (AML). We propose to study how these molecules cause disease, and determine if blocking microRNAs can reduce AML in pre-clinical animal models. This work will provide novel insights into the contribution of microRNAs to different aspects of AML, and inform the development of next generation microRNA therapeutics that can be used to treat this devastating condition.

Lay Abstract

Mutations in genes that control cell growth and survival are commonly found in leukemia. In the case of acute myeloid leukemia (AML) there is often a mutation in a gene called FLT3 that causes it to be activated all the time and promote disease. However, there are many aspects of how this mutated gene is able to promote AML that remain unclear, making it challenging to design and develop new therapies against this devastating condition. My lab studies a newly discovered class of molecules, called microRNAs, which are altered in diseases such as leukemia. In the case of AML with FLT3 mutations, one particular microRNA, called miR-155, is inappropriately elevated and thought to contribute to disease characteristics, including resistance to chemotherapy. Indeed, our preliminary results indicate that when miR-155 is reduced, many symptoms of leukemia that are caused by FLT3 are alleviated in mice and human AML cells growing in a dish. This suggests that miR-155 might work with FLT3 mutations to drive some types of AML in the clinic. We propose to study this relationship in greater detail to understand how these molecules collaborate to cause disease, unveil the mechanisms that are controlled by these genes at the molecular level, and determine if inhibition of miR-155, or other candidate microRNAs, can reduce AML disease in pre-clinical mouse models. Together, this work will provide novel insights into the contribution of microRNAs to different aspects of AML with FLT3 mutations, and hopefully inform the development of next generation microRNA therapeutics that can be used to treat this devastating disease.

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