Effect of methotrexate/vitamin B12 on DNA methylation as a potential factor in leukemia treatment-related neurotoxicity

Epigenomics. 2017 Sep;9(9):1205-1218. doi: 10.2217/epi-2016-0165. Epub 2017 Aug 15.

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.

Results: MTX 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).

Conclusion: We 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.

Keywords: childhood acute lymphoblastic leukemia; epigenetic; late effects; methotrexate; neurocognition; neurotoxicity; one carbon metabolism; vitamin B12.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity
  • Cell Line, Tumor
  • DNA Methylation / drug effects*
  • Humans
  • Long Interspersed Nucleotide Elements
  • Methotrexate / adverse effects
  • Methotrexate / pharmacology*
  • Methotrexate / therapeutic use
  • Methotrexate / toxicity
  • Neurons / drug effects*
  • Neurotoxicity Syndromes / etiology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism
  • Vitamin B 12 / adverse effects
  • Vitamin B 12 / pharmacology*
  • Vitamin B 12 / therapeutic use
  • Vitamin B 12 / toxicity

Substances

  • Antineoplastic Agents
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 5
  • Vitamin B 12
  • Methotrexate