Originally published as JCO Early Release 10.1200/JCO.2008.19.3441 on January 21 2009

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Epigenetic Regulation of MicroRNAs in Acute Lymphoblastic Leukemia

Jose Roman-Gomez, Xabier Agirre, Antonio Jiménez-Velasco, Victor Arqueros, Amaia Vilas-Zornoza, Paula Rodriguez-Otero, Iñaki Martin-Subero, Leire Garate, Lucia Cordeu, Edurne San José-Eneriz, Vanesa Martin, Juan Antonio Castillejo, Eva Bandrés, María José Calasanz, Reiner Siebert, Anabel Heiniger, Antonio Torres, Felipe Prosper

From the Hematology Department, Reina Sofia Hospital, Cordoba; Hematology Department, Cellular Therapy Area, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research; Department of Genetics, University of Navarra, Pamplona; Hematology Department, Carlos Haya Hospital, Malaga, Spain; and the Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Abrechts University Kiel, Germany.

Corresponding author: Jose Roman-Gomez, MD, Hematology Department. Reina Sofia Hospital. Avda. Menendez Pidal s/n. 14004 Cordoba. Spain; e-mail: peperosa{at}teleline.es.

Purpose To identify microRNAs (miRNAs) epigenetically regulated in acute lymphoblastic leukemia (ALL).

Methods We first examined ALL-derived cell lines for the presence of abnormal levels of two different histone modifications (trimethylation of H3 lysine 4 [K4H3me3] and dimethylation of H3 lysine 9 [K9H3me2]) in the 5'UTR regions around CpG islands of 78 miRNAs by chromatin immunoprecipitation (ChIP)-on-ChIP analysis. Methylation status (methylation-specific polymerase chain reaction [PCR]) and expression (quantitative PCR) of miRNAs showing a pattern of histone modifications linked to a closed chromatin structure were analyzed in a panel of six ALL cell lines and in 353 ALL patients.

Results CpG islands around 13 miRNAs disclosed high levels of K9H3me2 and/or low levels of K4H3me3, a pattern of histone modifications underlying a closed chromatin structure associated with repressive gene expression. Complete consistency in the correlation between both histone marks, the presence of DNA methylation around these miRNAs, and their expression patterns was confirmed in the six ALL cell lines. Treatment with 5-Aza-2'-deoxycytidine upregulated the expression levels of these genes, suggesting that epigenetic mechanisms deregulate the expression of these miRNAs. A total of 65% of the ALL samples had at least one miRNA methylated (methylated group). Estimated disease-free survival (DFS) and overall survival (OS) at 14 years were 78% and 71% for nonmethylated patients and 24% and 28% for methylated patients (P = .00001 for both). Multivariate analysis demonstrated that methylation profile was an independent prognostic factor for predicting DFS (P = .0001) and OS (P = .0001).

Conclusion Aberrant miRNA methylation is a common phenomenon in ALL that affects the clinical outcome of these patients.

J.R.-G. and X.A. contributed equally to this work.

Supported by grants from Beca Ortiz de Landázuri 2006, Departamento de Salud-Gobierno de Navarra; Grants No. PI070602, PI070608, PI060003, CP07/00215, and RD06/0020 from the Fondo de Investigación Sanitaria (Spain); Grants No. 0386/2006 and 0004/2007 from Junta de Andalucia; Kinder-Krebs-Initiative Buchholz, Holm-Seppensen (K.K.I.) and funds from AMI and "UTE project CIMA".

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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