Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels

Background: Wilms tumor 1 (WT1) is over-expressed in numerous cancers with respect to normal cells, and has either a tumor suppressor or oncogenic role depending on cellular context. This gene is associated with numerous alternatively spliced transcripts, which initiate from two different unique fir...

Descripción completa

Detalles Bibliográficos
Autores: Guillaumet Adkins, Amy, Richter, Julia, Odero, Maria D., Sandoval, Juan, Agirre, Xabier, Català Temprano, Albert, Esteller, Manel, Prósper, Felipe, Calasanz, María José, Buño, Ismael, Kwo, Mi, Court, Franck, Siebert, Reiner, Monk, David
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/125947
Acceso en línea:https://hdl.handle.net/2445/125947
Access Level:acceso abierto
Palabra clave:Metilació
Epigenètica
Leucèmia mieloide
Methylation
Epigenetics
Myeloid leukemia
id ES_fc4bb30c6ef93a45f8ebe2c0e8d7b52a
oai_identifier_str oai:recercat.cat:2445/125947
network_acronym_str ES
network_name_str España
repository_id_str
spelling Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levelsGuillaumet Adkins, AmyRichter, JuliaOdero, Maria D.Sandoval, JuanAgirre, XabierCatalà Temprano, AlbertEsteller, ManelPrósper, FelipeCalasanz, María JoséBuño, IsmaelKwo, MiCourt, FranckSiebert, ReinerMonk, DavidMetilacióEpigenèticaLeucèmia mieloideMethylationEpigeneticsMyeloid leukemiaBackground: Wilms tumor 1 (WT1) is over-expressed in numerous cancers with respect to normal cells, and has either a tumor suppressor or oncogenic role depending on cellular context. This gene is associated with numerous alternatively spliced transcripts, which initiate from two different unique first exons within the WT1 and the alternative (A) WT1 promoter intervals. Within the hematological system, WT1 expression is restricted to CD34+/ CD38- cells and is undetectable after differentiation. Detectable expression of this gene is an excellent marker for minimal residual disease in acute myeloid leukemia (AML), but the underlying epigenetic alterations are unknown. Methods: To determine the changes in the underlying epigenetic landscape responsible for this expression, we characterized expression, DNA methylation and histone modification profiles in 28 hematological cancer cell lines and confirmed the methylation signature in 356 cytogenetically well-characterized primary hematological malignancies. Results: Despite high expression of WT1 and AWT1 transcripts in AML-derived cell lines, we observe robust hypermethylation of the AWT1 promoter and an epigenetic switch from a permissive to repressive chromatin structure between normal cells and AML cell lines. Subsequent methylation analysis in our primary leukemia and lymphoma cohort revealed that the epigenetic signature identified in cell lines is specific to myeloid-lineage malignancies, irrespective of underlying mutational status or translocation. In addition to being a highly specific marker for AML diagnosis (positive predictive value 100%; sensitivity 86.1%; negative predictive value 89.4%), we show that AWT1 hypermethylation also discriminates patients that relapse from those achieving complete remission after hematopoietic stem cell transplantation, with similar efficiency to WT1 expression profiling. Conclusions: We describe a methylation signature of the AWT1 promoter CpG island that is a promising marker for classifying myeloid-derived leukemias. In addition AWT1 hypermethylation is ideally suited to monitor the recurrence of disease during remission in patients undergoing allogeneic stem cell transfer.BioMed Central2018201820142018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/2445/125947Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/1756-8722-7-4Journal of Hematology & Oncology, 2014, vol. 7, p. 4https://doi.org/10.1186/1756-8722-7-4info:eu-repo/grantAgreement/EC/FP7/282510cc-by (c) Guillaumet Adkins, Amy et al., 2014http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1259472026-05-29T05:05:01Z
dc.title.none.fl_str_mv Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
title Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
spellingShingle Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
Guillaumet Adkins, Amy
Metilació
Epigenètica
Leucèmia mieloide
Methylation
Epigenetics
Myeloid leukemia
title_short Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
title_full Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
title_fullStr Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
title_full_unstemmed Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
title_sort Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels
dc.creator.none.fl_str_mv Guillaumet Adkins, Amy
Richter, Julia
Odero, Maria D.
Sandoval, Juan
Agirre, Xabier
Català Temprano, Albert
Esteller, Manel
Prósper, Felipe
Calasanz, María José
Buño, Ismael
Kwo, Mi
Court, Franck
Siebert, Reiner
Monk, David
author Guillaumet Adkins, Amy
author_facet Guillaumet Adkins, Amy
Richter, Julia
Odero, Maria D.
Sandoval, Juan
Agirre, Xabier
Català Temprano, Albert
Esteller, Manel
Prósper, Felipe
Calasanz, María José
Buño, Ismael
Kwo, Mi
Court, Franck
Siebert, Reiner
Monk, David
author_role author
author2 Richter, Julia
Odero, Maria D.
Sandoval, Juan
Agirre, Xabier
Català Temprano, Albert
Esteller, Manel
Prósper, Felipe
Calasanz, María José
Buño, Ismael
Kwo, Mi
Court, Franck
Siebert, Reiner
Monk, David
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Metilació
Epigenètica
Leucèmia mieloide
Methylation
Epigenetics
Myeloid leukemia
topic Metilació
Epigenètica
Leucèmia mieloide
Methylation
Epigenetics
Myeloid leukemia
description Background: Wilms tumor 1 (WT1) is over-expressed in numerous cancers with respect to normal cells, and has either a tumor suppressor or oncogenic role depending on cellular context. This gene is associated with numerous alternatively spliced transcripts, which initiate from two different unique first exons within the WT1 and the alternative (A) WT1 promoter intervals. Within the hematological system, WT1 expression is restricted to CD34+/ CD38- cells and is undetectable after differentiation. Detectable expression of this gene is an excellent marker for minimal residual disease in acute myeloid leukemia (AML), but the underlying epigenetic alterations are unknown. Methods: To determine the changes in the underlying epigenetic landscape responsible for this expression, we characterized expression, DNA methylation and histone modification profiles in 28 hematological cancer cell lines and confirmed the methylation signature in 356 cytogenetically well-characterized primary hematological malignancies. Results: Despite high expression of WT1 and AWT1 transcripts in AML-derived cell lines, we observe robust hypermethylation of the AWT1 promoter and an epigenetic switch from a permissive to repressive chromatin structure between normal cells and AML cell lines. Subsequent methylation analysis in our primary leukemia and lymphoma cohort revealed that the epigenetic signature identified in cell lines is specific to myeloid-lineage malignancies, irrespective of underlying mutational status or translocation. In addition to being a highly specific marker for AML diagnosis (positive predictive value 100%; sensitivity 86.1%; negative predictive value 89.4%), we show that AWT1 hypermethylation also discriminates patients that relapse from those achieving complete remission after hematopoietic stem cell transplantation, with similar efficiency to WT1 expression profiling. Conclusions: We describe a methylation signature of the AWT1 promoter CpG island that is a promising marker for classifying myeloid-derived leukemias. In addition AWT1 hypermethylation is ideally suited to monitor the recurrence of disease during remission in patients undergoing allogeneic stem cell transfer.
publishDate 2014
dc.date.none.fl_str_mv 2014
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/125947
url https://hdl.handle.net/2445/125947
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/1756-8722-7-4
Journal of Hematology & Oncology, 2014, vol. 7, p. 4
https://doi.org/10.1186/1756-8722-7-4
info:eu-repo/grantAgreement/EC/FP7/282510
dc.rights.none.fl_str_mv cc-by (c) Guillaumet Adkins, Amy et al., 2014
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Guillaumet Adkins, Amy et al., 2014
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425409022492672
score 15,81155

Similares en LA Referencia