Date of Award

4-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Molecular and Systems Pharmacology

Research Advisor

William E. Evans, PharmD

Committee

Taosheng Chen, PhD; Charles G. Mullighan, MD; Mary V. Relling, PharmD; Robert Williams, PhD

Keywords

Drug Resistance, Genomics, Glucocorticoids, Leukemia, Pharmacogenomics

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Much has been discovered in recent decades regarding ALL biology, and the outcome of patients with ALL has vastly improved, especially in pediatric ALL patients. Despite very promising overall cure rates, patients who relapse have a greatly decreased prognosis with survival rates ranging from 30-60%. These numbers stand to improve even further with new targeted therapies that seek to improve or maintain cure rates while reducing treatment related toxicities which affect patients both acutely and chronically. Glucocorticoids (GCs) are essential components of modern chemotherapeutic intervention for ALL. Resistance to glucocorticoids is an important factor in determining early treatment response and overall patient survival. Reduction of glucocorticoid induced toxicities, such as osteonecrosis, can significantly affect patient quality of life and are associated with high dose glucocorticoid treatment in pediatric patients. Both endogenous and exogenous glucocorticoids exert their mechanism of action through various pleiotropic effects that regulate numerous cellular functions and can cause selective cytotoxicity in lymphoid malignancies. The complex mechanism of action of glucocorticoids is evident in the number of diverse clinically relevant molecular pathways that have been previously associated with resistance to glucocorticoids in ALL.The identification of genomic and epigenomic mechanisms of glucocorticoid resistance are important for improving ALL treatment outcomes. We used an agnostic genome-wide method to interrogate multiple types of genomic information (mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels) in primary human acute lymphoblastic leuke

ORCID

https://orcid.org/0000-0002-6965-2942

DOI

10.21007/etd.cghs.2020.0501

Additional Files
2020-010-Autry-DOA.pdf (418 kB)
Declaration of Authorship
2020-010-Autry-SupplementaryTables1-9.xlsx (25177 kB)
Supplemental Tables 1-9
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