Effect of Methotrexate/Vitamin B ₁₂ on DNA Methylation as a Potential Factor in Leukemia Treatment-Related Neurotoxicity

Abstract

Methotrexate (MTX) is administered to treat childhood acute lymphoblastic leukemia (ALL). It acts by inhibiting dihydrofolate reductase which reduces methyltetrahydrofolate, a key component in one carbon metabolism, thus reducing cell proliferation. Further perturbations to one carbon metabolism, such as reduced vitamin B12 levels via the use of nitrous oxide for sedation during childhood ALL treatment, may increase neurotoxicity risk. With B12 as an enzymatic cofactor, methyltetrahydrofolate is essential to produce methionine, which is critical for DNA methylation. We investigated global and gene specific DNA methylation in neuronal cell lines in response to MTX treatment and vitamin B12 concentration individually, and in combination.ResultsMTX treatment alone significantly increased LINE-1 methylation in SH-SY5Y (p = 0.040) and DAOY (p < 0.001), and increased FKBP5 methylation in MO3.13 cells (p = 0.009).ConclusionWe conclude that altered DNA methylation of brain/central nervous system cells could be one mechanism involved in MTX treatment-related neurotoxicities and neurocognitive late effects in ALL survivors.

Potential contributors to low dose methotrexate toxicity in a patient with rheumatoid arthritis and pernicious anemia: case report

“…Less commonly, pancytopenia may ensue. Our patient’s pancytopenia may have been accentuated by her vitamin B12 deficiency [ 23 – 25 ].…”

Methotrexate Associated Toxicity: An Alarming Benign Entity

“…Some drugs such as trimethoprim/sulfamethoxazole, non-steroidal anti-inflammatory drugs, penicillin, proton pump inhibitors, acetylsalicylic acid and nitric oxide can lead to a delayed MTX clearance and increase its neurotoxicity; for these reasons they have to be avoided before and after the MTX administration on high doses [5,7,8] (Figure 1 The neurotoxicity induced by the MTX can be acute, subacute or chronic. It's pointed out that can develop also cases of asymptomatic leukoencephalopathy that could persist exactly after completing the treatment [1].…”

Random epigenetic modulation of CHO cells by repeated knockdown of DNA methyltransferases increases population diversity and enables sorting of cells with higher production capacities

“…Moreover, one commonly used chemical to achieve selection in CHO is methotrexate (MTX). MTX interacts and influences the formation of the cosubstrate molecule S‐Adenosyl methionine required for methylation of cytosines (Forster, McDonnell, Theobald, & McKay, 2017). This suggests that potentially the actual success of this selection system was enhanced by the combination of gene amplification and epigenetic changes.…”