Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

Natanja Oosterom; Pieter H. Griffioen; Marissa A.H. Den Hoed; Rob Pieters; Robert De Jonge; Wim J.E. Tissing; Marry M. Van Den Heuvel-Eibrink; Sandra G. Heil

doi:10.1371/journal.pone.0199574

Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

Natanja Oosterom^*, Pieter H. Griffioen, Marissa A.H. Den Hoed, Rob Pieters, Robert De Jonge, Wim J.E. Tissing, Marry M. Van Den Heuvel-Eibrink, Sandra G. Heil

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

2 Citations (Scopus)

Abstract

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis.

MATERIALS & METHODS: S-Adenosyl-Methionine (SAM) and S-Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade ≥ 3 National Cancer Institute Criteria) was used as clinical endpoint.

RESULTS: SAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 -+46.0), p<0.001), while SAH levels and the SAM:SAH ratio did not change significantly. LINE1 DNA methylation (+1.4% (-1.1 -+6.5), p<0.001) increased during therapy. SAM and SAH levels were not correlated to LINE1 DNA methylation status. No association was found between DNA methylation markers and developing oral mucositis.

CONCLUSIONS: This was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis.

Original language	English
Article number	e0199574
Pages (from-to)	e0199574
Journal	PLoS ONE
Volume	13
Issue number	7
DOIs	https://doi.org/10.1371/journal.pone.0199574
Publication status	Published - 1 Jul 2018

Keywords

Adolescent
Antimetabolites, Antineoplastic/adverse effects
Child
Child, Preschool
DNA Methylation
Female
Humans
Immunophenotyping
Infant
Long Interspersed Nucleotide Elements
Male
Metabolic Networks and Pathways
Methotrexate/adverse effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications
S-Adenosylmethionine/blood
Stomatitis/etiology

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@article{237b5c3ff5fe40a6958fa0fac91bd093,

title = "Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia",

abstract = "BACKGROUND: Children with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis.MATERIALS & METHODS: S-Adenosyl-Methionine (SAM) and S-Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade ≥ 3 National Cancer Institute Criteria) was used as clinical endpoint.RESULTS: SAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 -+46.0), p<0.001), while SAH levels and the SAM:SAH ratio did not change significantly. LINE1 DNA methylation (+1.4% (-1.1 -+6.5), p<0.001) increased during therapy. SAM and SAH levels were not correlated to LINE1 DNA methylation status. No association was found between DNA methylation markers and developing oral mucositis.CONCLUSIONS: This was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis.",

keywords = "Adolescent, Antimetabolites, Antineoplastic/adverse effects, Child, Child, Preschool, DNA Methylation, Female, Humans, Immunophenotyping, Infant, Long Interspersed Nucleotide Elements, Male, Metabolic Networks and Pathways, Methotrexate/adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications, S-Adenosylmethionine/blood, Stomatitis/etiology",

author = "Natanja Oosterom and Griffioen, {Pieter H.} and {Den Hoed}, {Marissa A.H.} and Rob Pieters and {De Jonge}, Robert and Tissing, {Wim J.E.} and {Van Den Heuvel-Eibrink}, {Marry M.} and Heil, {Sandra G.}",

note = "Funding Information: This project was supported by Stichting Kinderen Kankervrij, Amstelveen, The Netherlands, grant number 197. This grant was received by SGH and MMvdHE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2018 Oosterom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2018",

month = jul,

day = "1",

doi = "10.1371/journal.pone.0199574",

language = "English",

volume = "13",

pages = "e0199574",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "7",

}

TY - JOUR

T1 - Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

AU - Oosterom, Natanja

AU - Griffioen, Pieter H.

AU - Den Hoed, Marissa A.H.

AU - Pieters, Rob

AU - De Jonge, Robert

AU - Tissing, Wim J.E.

AU - Van Den Heuvel-Eibrink, Marry M.

AU - Heil, Sandra G.

N1 - Funding Information: This project was supported by Stichting Kinderen Kankervrij, Amstelveen, The Netherlands, grant number 197. This grant was received by SGH and MMvdHE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2018 Oosterom et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - BACKGROUND: Children with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis.MATERIALS & METHODS: S-Adenosyl-Methionine (SAM) and S-Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade ≥ 3 National Cancer Institute Criteria) was used as clinical endpoint.RESULTS: SAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 -+46.0), p<0.001), while SAH levels and the SAM:SAH ratio did not change significantly. LINE1 DNA methylation (+1.4% (-1.1 -+6.5), p<0.001) increased during therapy. SAM and SAH levels were not correlated to LINE1 DNA methylation status. No association was found between DNA methylation markers and developing oral mucositis.CONCLUSIONS: This was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis.

AB - BACKGROUND: Children with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis.MATERIALS & METHODS: S-Adenosyl-Methionine (SAM) and S-Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade ≥ 3 National Cancer Institute Criteria) was used as clinical endpoint.RESULTS: SAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 -+46.0), p<0.001), while SAH levels and the SAM:SAH ratio did not change significantly. LINE1 DNA methylation (+1.4% (-1.1 -+6.5), p<0.001) increased during therapy. SAM and SAH levels were not correlated to LINE1 DNA methylation status. No association was found between DNA methylation markers and developing oral mucositis.CONCLUSIONS: This was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis.

KW - Adolescent

KW - Antimetabolites, Antineoplastic/adverse effects

KW - Child

KW - Child, Preschool

KW - DNA Methylation

KW - Female

KW - Humans

KW - Immunophenotyping

KW - Infant

KW - Long Interspersed Nucleotide Elements

KW - Male

KW - Metabolic Networks and Pathways

KW - Methotrexate/adverse effects

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications

KW - S-Adenosylmethionine/blood

KW - Stomatitis/etiology

UR - http://www.scopus.com/inward/record.url?scp=85049552580&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0199574

DO - 10.1371/journal.pone.0199574

M3 - Article

C2 - 29985926

AN - SCOPUS:85049552580

SN - 1932-6203

VL - 13

SP - e0199574

JO - PLoS ONE

JF - PLoS ONE

IS - 7

M1 - e0199574

ER -

Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

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