Author ORCID Identifier
Date Available
5-4-2021
Year of Publication
2021
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Molecular and Cellular Biochemistry
First Advisor
Dr. Jessica S. Blackburn
Second Advisor
Dr. Doug Andres
Abstract
The survival rate of T-cell Acute Lymphoblastic Leukemia (T-ALL) relapse is a dismal 10% of affected adults and 30% of children, largely due to the relapsed disease being more aggressive and treatment resistant than the initial disease. Relapse is thought to occur because conventional chemotherapies are unable to reliably eliminate a unique cell type known as leukemia stem (or propagating) cells (LSCs). LSCs are the only cells within the leukemia with the ability to self-renew and remake or replenish the ALL from a single cell. Currently, the pathways governing self-renewal in LSCs are largely unknown, precluding our ability to successfully and selectively target this important cell type with anti-cancer drugs. More research is needed to identify targetable pathways and develop new technologies for studying LSCs.
Here, I determined that the oncogenic phosphatase of regenerating liver 3 (PRL-3) plays a role in leukemia progression, migration, and self-renewal of LSCs in T-ALL in vivo in a zebrafish Myc-induced T-ALL model, while inhibition of PRL-3 reduced LSC numbers in vivo and in vitro. RNA sequencing and GSEA of patient T-ALL samples revealed that PRL-3’s role in self-renewal is at least partly due to activation of Wnt pathway signaling, a known driver of LSC function in T-ALL. While the Wnt pathway seems an ideal target for LSCs, Wnt signaling is critical for many normal and developmental processes. Clinical trials for Wnt inhibitors have shown undesirable toxicity and these drugs are not practical for use in children with T-ALL due to developmental concerns. Thus, a major gap in knowledge concerning leukemia stem cells in T-ALL is the identification of regulators of Wnt signaling, like PRL-3, that are uniquely expressed by leukemia cells and easily targeted with small molecules. To expand my research beyond PRL-3, I have developed a novel zebrafish T-ALL model where Wnt expressing cells fluorescently labeled. These animals can be used as a model for studying LSC function and identifying novel drugs that can target Wnt-expressing T-ALL cells in vivo.
I have also developed novel translational technologies that may be used to predict LSC driven relapse in T-ALL. I have optimized a zebrafish larval xenograft model for transplant and rapid drug screening of human T-ALL cell lines and patient samples to gain insight into tumor progression and resistance to chemotherapy. I have also developed a novel pipeline for using cell-free circulating tumor DNA (ctDNA) as a biomarker of disease relapse in patients with ALL, enabling tracking of disease course, assessment of minimal residual disease, and as a potential predictor of patient relapse.
Taken together, my research has established PRL-3 as a potential therapeutic target in T-ALL, and provided new insight into the role of a PRL-3/Wnt signaling axis in regulating LSC self-renewal. Additionally, the new models and techniques that I have developed are useful tools in analyzing LSC function, targeting self-renewal, and predicting ALL relapse.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2021.133
Funding Information
This study was supported by the National Institutes of Health Training Grant T32CA165990 from 2018-2021.
Recommended Citation
Haney, Meghan G., "Therapeutic Targeting of Leukemia Stem Cells to Prevent T-Cell Acute Lymphoblastic Leukemia Relapse" (2021). Theses and Dissertations--Molecular and Cellular Biochemistry. 52.
https://uknowledge.uky.edu/biochem_etds/52
