Roles of Oxidative Stress and Dna Methylation In Cigarette Smoking-Induced Accelerated Acute Myeloid Leukemia Progression

<p>Acute myeloid leukemia (AML) is a commonly diagnosed cancer in smokers. When current or former smokers have AML, they have worse survival compared to never smoking patients. This has been observed clinically for decades, but then it is unknown how smoking leads to worsened AML survival. Smoking causes oxidative stress and altered DNA methylation that persists for decades in peripheral blood mononuclear cells, but these changes from smoking have not been evaluated in the context of AML. We hypothesize that smoking-induced molecular changes, including altered DNA methylation associated with poor AML prognosis, promote AML. We developed a novel model to study cigarette smoke exposure (SE) in AML-bearing mice. Using our model, we investigated the impact of SE on AML progression and how smoking cessation compared to continued SE. Cigarette smoke condensate (CSC) treatment of AML cells in vitro was used to study how chemicals from cigarette smoke in the absence of high heat combustion directly impact AML cells. Our SE model and CSC treated AML cells resulted in accelerated leukemic progression in mice. SE and CSC exposed AML cells were examined for altered DNA methylation and for oxidative stress. Evaluation of nonsmoking and SE samples revealed changes in protein expression involved in AML progression viii and treatment resistance. This work shows that cigarette smoking enhances leukemic progression, induces oxidative stress in AML, alters DNA methylation that is associated with poor prognosis in AML, alters the bone marrow microenvironment to promote the growth of myeloid progenitor cells, and activates oncogenic signaling in AML cells. My work highlights the potential for using smoking as a behavioral biomarker to help tailor treatment in AML patients.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• Figueroa, Mary
• <p><a href="https://orcid.org/0000-0001-7926-4532">0000-0001-7926-4532</a></p>

Contributors dc:contributor

• Joya Chandra, Ph.D.
• Marcos R. Estecio, Ph.D.
• Marina Konopleva, M.D. Ph.D.

• Acute myeloid leukemia
• leukemia
• smoking
• DNA methylation
• AML
• oxidative stress
• Cancer Biology
• Cell Biology
• Other Genetics and Genomics
• Other Pharmacology, Toxicology and Environmental Health
• Pharmacology
• Therapeutics
• Toxicology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1218

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2275