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Neuroepigenetic Changes and Their Influence on Bortezomib-Induced Peripheral Neuropathy

By: Justine Landin, PhD
Posted: Thursday, June 2, 2022

Bortezomib-induced peripheral neuropathy is observed in approximately 40% of patients with multiple myeloma and may be mediated by transient epigenetic alterations, according to Bogusław Machaliński, MD, of Pomeranian Medical University, Szczecin, Poland, and colleagues. In fact, multiple disruptions in neuroepigenetic processes associated with chromatin rearrangement and silencing were found in patients with bortezomib-induced peripheral neuropathy and multiple myeloma. The findings of this study were published in the International Journal of Molecular Sciences.

“Perhaps counteracting the emerging epigenetic change in nerve cells would stop the entire cascade of dysregulation and reduce/eliminate the development of polyneuropathy. The next step will be to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of peripheral neuropathy,” stated the study investigators.

Human neuronal precursor cells derived from the Lund human mesencephalic cell line were differentiated into neurons and then treated with either bortezomib (0.15 nM, four times) or not treated. RNA and histone isolation were then performed, and miRNA microarray, enzyme-linked immunosorbent assay, and western blot analyses were used to identify epigenetic alterations within the corresponding genes and proteins.

Acetylation of global histone H3 and histone H3 lysine 9 was observed in neurons following low-dose bortezomib administration. Further, gene set enrichment analysis indicated the SIRT1, B-WICH, and b-catenin neuropathy–associated signaling pathways were associated with bortezomib. Additionally, genes that interact with miR-6810-5p, such as MSN, FOXM1, TSPAN9, and SLC1A5, were altered in the neural bortezomib group but not in the control group. These genes are involved in neuroprotection, neural differentiation, and signal transduction.

The authors concluded: “The study confirmed the existence of bortezomib-induced complex epigenetic alterations in nerve cells. However, further studies are necessary to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of [peripheral neuropathy].”

Disclosure: The study authors reported no conflicts of interest.

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