Cargando…
Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia
Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051212/ https://www.ncbi.nlm.nih.gov/pubmed/24280869 http://dx.doi.org/10.1038/leu.2013.362 |
_version_ | 1782320077686702080 |
---|---|
author | Jost, E Lin, Q Weidner, C I Wilop, S Hoffmann, M Walenda, T Schemionek, M Herrmann, O Zenke, M Brümmendorf, T H Koschmieder, S Wagner, W |
author_facet | Jost, E Lin, Q Weidner, C I Wilop, S Hoffmann, M Walenda, T Schemionek, M Herrmann, O Zenke, M Brümmendorf, T H Koschmieder, S Wagner, W |
author_sort | Jost, E |
collection | PubMed |
description | Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A, which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A. Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen. |
format | Online Article Text |
id | pubmed-4051212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-40512122014-06-13 Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia Jost, E Lin, Q Weidner, C I Wilop, S Hoffmann, M Walenda, T Schemionek, M Herrmann, O Zenke, M Brümmendorf, T H Koschmieder, S Wagner, W Leukemia Original Article Mutations in the genetic sequence of the DNA de novo methyltransferase DNMT3A (DNA methyltransferase 3A) are found in many patients with acute myeloid leukemia (AML). They lead to dysfunction of DNMT3A protein and represent a marker for poor prognosis. Effects of genetic mutations can be mimicked by epigenetic modifications in the DNA methylation (DNAm) pattern. Using DNAm profiles of the Cancer Genome Atlas Research Network (TCGA), we identified aberrant hypermethylation at an internal promoter region of DNMT3A, which occurred in about 40% of AML patients. Bisulfite pyrosequencing assays designed for this genomic region validated hypermethylation specifically in a subset of our AML samples. High DNAm levels at this site are particularly observed in samples without genetic mutations in DNMT3A. Epimutations and mutations of DNMT3A were associated with related gene expression changes such as upregulation of the homeobox genes in HOXA and HOXB clusters. Furthermore, epimutations in DNMT3A were enriched in patients with poor or intermediate cytogenetic risk, and in patients with shorter event-free survival and overall survival (OS). Taken together, aberrant DNA hypermethylation within the DNMT3A gene, in analogy to DNMT3A mutations, is frequently observed in AML and both modifications seem to be useful for risk stratification or choice of therapeutic regimen. Nature Publishing Group 2014-06 2013-12-20 /pmc/articles/PMC4051212/ /pubmed/24280869 http://dx.doi.org/10.1038/leu.2013.362 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by/3.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Original Article Jost, E Lin, Q Weidner, C I Wilop, S Hoffmann, M Walenda, T Schemionek, M Herrmann, O Zenke, M Brümmendorf, T H Koschmieder, S Wagner, W Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia |
title | Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia |
title_full | Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia |
title_fullStr | Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia |
title_full_unstemmed | Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia |
title_short | Epimutations mimic genomic mutations of DNMT3A in acute myeloid leukemia |
title_sort | epimutations mimic genomic mutations of dnmt3a in acute myeloid leukemia |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051212/ https://www.ncbi.nlm.nih.gov/pubmed/24280869 http://dx.doi.org/10.1038/leu.2013.362 |
work_keys_str_mv | AT joste epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT linq epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT weidnerci epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT wilops epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT hoffmannm epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT walendat epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT schemionekm epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT herrmanno epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT zenkem epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT brummendorfth epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT koschmieders epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia AT wagnerw epimutationsmimicgenomicmutationsofdnmt3ainacutemyeloidleukemia |