Forster Victoria J, McDonnell Alex, Theobald Rachel, McKay Jill A
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Institute of Health & Society, Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, UK.
Epigenomics. 2017 Sep;9(9):1205-1218. doi: 10.2217/epi-2016-0165. Epub 2017 Aug 15.
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 B levels via the use of nitrous oxide for sedation during childhood ALL treatment, may increase neurotoxicity risk. With B 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 B concentration individually, and in combination.
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).
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.
甲氨蝶呤（MTX）用于治疗儿童急性淋巴细胞白血病（ALL）。它通过抑制二氢叶酸还原酶发挥作用，该酶可还原甲基四氢叶酸，而甲基四氢叶酸是一碳代谢的关键成分，从而减少细胞增殖。对一碳代谢的进一步干扰，例如在儿童ALL治疗期间使用一氧化二氮镇静导致维生素B水平降低，可能会增加神经毒性风险。作为一种酶辅因子，甲基四氢叶酸对于生成蛋氨酸至关重要，而蛋氨酸对DNA甲基化至关重要。我们分别研究了神经元细胞系中整体和基因特异性DNA甲基化对MTX治疗以及维生素B浓度的反应，以及两者联合作用的反应。
单独使用MTX治疗显著增加了SH-SY5Y细胞系中LINE-1的甲基化（p = 0.040）和DAOY细胞系中LINE-1的甲基化（p < 0.001），并增加了MO3.13细胞中FKBP5的甲基化（p = 0.009）。
我们得出结论，脑/中枢神经系统细胞DNA甲基化的改变可能是ALL幸存者中与MTX治疗相关的神经毒性和神经认知远期效应所涉及的一种机制。
