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Background   TP53  mutation/deletion is uncommon in chronic lymphocytic leukemia (CLL). We postulated that components of TP53-centered tumor suppressor network,  miR-34b/c , in addition to  DAPK1  and  miR-34a  might be inactivated by DNA hypermethylation. Moreover, we tested if  miR-34b/c  methylation might correlate with  miR-203  or  miR-124-1  methylation in CLL.    Methods   miR-34b/c ,  miR-34a  and  DAPK1  methylation was studied in 11 normal controls, 7 CLL cell lines, and 78 diagnostic CLL samples by methylation-specific polymerase chain reaction. MEC-1 cells were treated with 5-Aza-2’-deoxycytidine for reversal of methylation-associated miRNA silencing. Tumor suppressor properties of  miR-34b  were demonstrated by over-expression of precursor  miR-34b  in MEC-1 cells.    Results   miR-34b/c  promoter was unmethylated in normal controls, but completely methylated in 4 CLL cell lines.  miR-34b/c  expression was inversely correlated with  miR-34b/c  methylation. Different MSP statuses of  miR-34b/c , including complete methylation and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. 5-Aza-2’-deoxycytidine treatment resulted in promoter demethylation and  miR-34b  re-expression in MEC1 cells. Moreover, over-expression of  miR-34b  resulted in inhibition of cellular proliferation and increased cell death. In primary CLL samples,  miR-34a ,  miR-34b/c  and  DAPK1  methylation was detected in 2.6%, 17.9% and 34.6% of patients at diagnosis respectively. Furthermore, 39.7%, 3.8% and 2.6% patients had methylation of one, two or all three genes respectively. Overall, 46.2% patients had methylation of at least one of these three genes. Besides,  miR-34b/c  methylation was associated with methylation of  miR-34a  (P = 0.03) and  miR-203  (P = 0.012) in CLL.    Conclusions  Taken together,  miR-34b/c  is a tumor suppressor miRNA frequently methylated, and hence silenced in CLL. Together with  DAPK1  methylation,  miR-34b/c  methylation is implicated in the disruption of the TP53-centered tumor suppressor network. Moreover, the association of miRNA methylation warrants further study.

Epigenetic inactivation of mir-34b/c in addition to mir-34a and DAPK1 in chronic lymphocytic leukemia