Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia

• Published in: Epigenetics Vol. 6; no. 2; pp. 188 - 194
• Main Authors: Fabris, Sonia, Bollati, Valentina, Agnelli, Luca, Morabito, Fortunato, Motta, Valeria, Cutrona, Giovanna, Matis, Serena, Grazia Recchia, Anna, Gigliotti, Vincenzo, Gentile, Massimo, Deliliers, Giorgio Lambertenghi, Bertazzi, Pier Alberto, Ferrarini, Manlio, Neri, Antonino, Baccarelli, Andrea
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.02.2011; Landes Bioscience
• Subjects: ADP-ribosyl Cyclase 1 - genetics; Adult; Aged; Aged, 80 and over; Alu; Alu Elements - genetics; B-Lymphocytes; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Centromere - genetics; chronic lymphocytic leukemia; Cycle; DNA Methylation; DNA methyltransferases; Female; Gene Expression Regulation, Leukemic; Humans; Immunoglobulin Heavy Chains - genetics; Landes; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; LINE-1; Long Interspersed Nucleotide Elements - genetics; Male; Membrane Glycoproteins - genetics; Middle Aged; Organogenesis; Prognosis; Proteins; Repetitive Sequences, Nucleic Acid - genetics; Research Paper; SAT-α; ZAP-70 Protein-Tyrosine Kinase - genetics
• ISSN: 1559-2294; 1559-2308
• DOI: 10.4161/epi.6.2.13528

Global DNA hypomethylation affecting repeat sequences has been reported in different cancer types. Herein, we investigated the methylation levels of repetitive DNA elements in chronic lymphocytic leukemia (CLL), their correlation with the major cytogenetic and molecular features, and clinical relevance in predicting therapy-free survival (TFS). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu, long interspersed nuclear elements-1 (LINE-1) and satellite-α (SAT-α) sequences in 77 untreated early-stage (Binet A) CLL patients. Peripheral B-cells from 7 healthy donors were used as controls. Methylation levels (median %5mC) were lower in B-CLLs compared with controls (21.4 vs. 25.9; 66.8 vs. 85.7; 84.0, vs. 88.2 for Alu, LINE-1 and SAT-α, respectively) (p < 0.001). Among CLL patients, a significant association was observed with 17p13.1 deletion (16.8 vs. 22.4; 51.2 vs. 68.5; 52.6 vs. 85.0, for Alu, LINE-1 and SAT-α) but not with other major genetic lesions, IgVH mutation status, CD38 or ZAP-70 expression. Follow-up analyses showed that lower SAT-α methylation levels appeared to be an independent prognostic marker significantly associated with shorter TFS. Our study extended previous limited evidences in methylation of repetitive sequences in CLL suggesting an important biological and clinical relevance in the disease.