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

PloS one (2011-03-10)
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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

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Anti-acetyl-Histone H3 Antibody, from rabbit
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Anti-p53 antibody, Mouse monoclonal, clone DO-1, purified from hybridoma cell culture
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Anti-Phosphotyrosine Antibody, clone 4G10®, clone 4G10®, Upstate®, from mouse