Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.

Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methy...

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Autores principales:	Amaia Vilas-Zornoza, Xabier Agirre, Vanesa Martín-Palanco, José Ignacio Martín-Subero, Edurne San José-Eneriz, Leire Garate, Sara Álvarez, Estíbaliz Miranda, Paula Rodríguez-Otero, José Rifón, Antonio Torres, María José Calasanz, Juan Cruz Cigudosa, José Román-Gómez, Felipe Prósper
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6e39c3a5691b497a9b4284448183bded
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spelling	oai:doaj.org-article:6e39c3a5691b497a9b4284448183bded2021-11-18T06:58:05ZFrequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.1932-620310.1371/journal.pone.0017012https://doaj.org/article/6e39c3a5691b497a9b4284448183bded2011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21386967/?tool=EBIhttps://doaj.org/toc/1932-6203Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2'-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.Amaia Vilas-ZornozaXabier AgirreVanesa Martín-PalancoJosé Ignacio Martín-SuberoEdurne San José-EnerizLeire GarateSara ÁlvarezEstíbaliz MirandaPaula Rodríguez-OteroJosé RifónAntonio TorresMaría José CalasanzJuan Cruz CigudosaJosé Román-GómezFelipe PrósperPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e17012 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Amaia Vilas-Zornoza Xabier Agirre Vanesa Martín-Palanco José Ignacio Martín-Subero Edurne San José-Eneriz Leire Garate Sara Álvarez Estíbaliz Miranda Paula Rodríguez-Otero José Rifón Antonio Torres María José Calasanz Juan Cruz Cigudosa José Román-Gómez Felipe Prósper Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.
description	Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2'-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.
format	article
author	Amaia Vilas-Zornoza Xabier Agirre Vanesa Martín-Palanco José Ignacio Martín-Subero Edurne San José-Eneriz Leire Garate Sara Álvarez Estíbaliz Miranda Paula Rodríguez-Otero José Rifón Antonio Torres María José Calasanz Juan Cruz Cigudosa José Román-Gómez Felipe Prósper
author_facet	Amaia Vilas-Zornoza Xabier Agirre Vanesa Martín-Palanco José Ignacio Martín-Subero Edurne San José-Eneriz Leire Garate Sara Álvarez Estíbaliz Miranda Paula Rodríguez-Otero José Rifón Antonio Torres María José Calasanz Juan Cruz Cigudosa José Román-Gómez Felipe Prósper
author_sort	Amaia Vilas-Zornoza
title	Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.
title_short	Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.
title_full	Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.
title_fullStr	Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.
title_full_unstemmed	Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.
title_sort	frequent and simultaneous epigenetic inactivation of tp53 pathway genes in acute lymphoblastic leukemia.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/6e39c3a5691b497a9b4284448183bded
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Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.

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