microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia

作者：Deneberg Stefan^*; Kanduri Meena; Ali Dina; Bengtzen Sofia; Karimi Mohsen; Qu Ying; Kimby Eva; Mansouri Larry; Rosenquist Richard; Lennartsson Andreas; Lehmann Soren

来源：Epigenetics, 2014, 9(6): 910-917.

DOI：10.4161/epi.28603

• chronic lymphatic leukemia
• micro-RNA
• DNA methylation
• epigenetics

A commonly deleted region in chronic lymphocytic leukemia (CLL) is the 11q22-23 region, which encompasses the ATM gene. Evidence suggests that tumor suppressor genes other than ATM are likely to be involved in CLL with del(11q). A microRNA (miR) cluster including the miR-34b and miR-34c genes is located, among other genes, within the commonly deleted region (CDR) at 11q. Interestingly, these miRs are part of the TP53 network and have been shown to be epigenetically regulated. In this study, we investigated the expression and methylation status of these miRs in a well-characterized cohort of CLL, including cases with/without 11q-deletion. We show that the miR-34b/c promoter was aberrantly hypermethylated in a large proportion of CLL cases (48%, 25/52 cases). miR-34b/c expression correlated inversely to DNA methylation (P = 0.003), and presence of high H3K37me3 further suppressed expression regardless of methylation status. Furthermore, increased miR-34b/c methylation inversely correlated with the presence of 11q-deletion, indicating that methylation and del(11q) independently silence these miRs. Finally, 5-azacytidine and trichostatin A exposure synergistically increased the expression of miR-34b/c in CLL cells, and transfection of miR-34b or miR-34c into HG3 CLL cells significantly increased apoptosis. Altogether, our novel data suggest that miR-34b/c is a candidate tumor suppressor that is epigenetically silenced in CLL.

• 出版日期2014-6