Abstract

Off-target neuronal injury is a serious side-effect observed in cancer survivors. It has previously been shown that pediatric acute lymphoblastic leukemia (ALL) survivors have a decline in neurocognition compared to healthy age-matched counterparts. Elevated oxidative stress has been documented to be a mediator in off- target tissue damage in cancer survivors. Early detection of oxidative stress markers may provide an opportunity to prevent off-target tissue damage. Extracellular vesicles (EVs) have surfaced as a potential diagnostic tool due to molecular cargo they contain. We investigated the potential for EVs to be a sensitive indicator of oxidative stress and off-target tissue damage by isolating EVs from pediatric ALL patients throughout their first 2 months of treatment. EVs were measured throughout the collection points for: 1) number of EV particles generated using nanoparticle tracking analysis (NTA); 2) markers of neurons (NeuN), astrocyte activation (GFAP), neuronal stability (BDNF), 3) markers of pre-B cell ALL (CD19 and CD22); and) 4-hydroxy-2-nonenal (HNE) adducted proteins. HNE protein adductions were measured in the patient sera and CSF. Pro-inflammatory cytokine levels were also measured in patient sera because of their contribution to oxidative stress and neuronal injury. Our results: 1) demonstrate EVs are a sensitive indicator of oxidative damage; 2) suggest EVs as a marker of a decline in neuronal stability; and 3) show the presence of leukemia has a greater contribution to pro-inflammatory cytokine production in the patient’s serum than the cancer treatment. Spe- cifically, we observed a significant decrease in cytokine levels (e.g., TNF-α, IL-1β, IL-6, and IL-8) following the initiation of treatment, highlighting the influence of leukemia burden on systemic inflammation. The results support the utilization of EVs as a sensitive marker of oxidative stress and off-target tissue damage.

Document Type

Article

Publication Date

2025

Notes/Citation Information

0891-5849/© 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.freeradbiomed.2024.12.006

Funding Information

The authors would like to acknowledge the Redox Metabolism Shared Resource Facility (Michael Alstott) for the HNE immunoblotting and the Biostatistics and Bioinformatics Shared Resource Facility at the Markey Cancer Center, and Jennifer Moylan of the Biomarker Analysis Lab at the Center for Clinical and Translational Science at the University of Kentucky, for the outstanding service. This work was supported, in part, by the National Institutes of Health (5R01CA217934), the National Institute of Environmental Health Sci- ences (T32ES07266), the National Cancer Institute (P30 CA177558, R01 CA251663), and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National In- stitutes of Health (UL1TR001998).

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