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Carcinogenesis

Year: 2009  |  Volume: 30  |  Issue: 8  |  Page No.: 1330 - 1335

Differential repetitive DNA methylation in multiple myeloma molecular subgroups

V Bollati, S Fabris, V Pegoraro, D Ronchetti, L Mosca, G. L Deliliers, V Motta, P. A Bertazzi, A Baccarelli and A. Neri

Abstract

Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT- in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT- (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-, respectively). Notably, LINE-1 and SAT- methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT- methylation was significantly lower in MMs with t(4;14) (P = 0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P < 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.

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