Precursor cell lymphoblastic leukemia-lymphoma/diagnosis/genetics/mortality Tumor Suppressor Protein p53/genetics/metabolism Gene Silencing/physiology
Public Library of Science
Vilas-Zornoza A, Agirre X, Martin-Palanco V, Martin-Subero JI, San Jose-Eneriz E, Garate L, et al. Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia. PLoS One 2011 Feb 28;6(2):e17012.
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-29-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.