Epigenetic inactivation of DAPK1, p14ARF, mir-34a and -34b/c in acute promyelocytic leukaemia

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Abstract

Aim

TP53 mutation frequently occurs in solid cancers but not haematological cancers including acute promyelocytic leukaemia (APL) characterised by t(15;17). Both DAPK1 and p14ARF positively regulate p53 whereas miR-34a and -34b/c are direct transcriptional targets of p53. We studied if DNA methylation might contribute to inactivation of gene/microRNA (miRNA) in the TP53 tumour suppressor network.

Methods

Promoter methylation of DAPK1, p14ARF, miR-34a and -34b/c were studied in 10 normal bone marrow samples, NB4 cell line and 60 APL primary samples at diagnosis by methylation-specific PCR (MSP).

Results

DAPK1, p14ARF, miR-34a and -34b/c were completely unmethylated in normal bone marrow samples. DAPK1, miR-34a and -34b/c were completely methylated in NB4. Treatment of NB4 by 5′-Aza-2′-deoxyctidine resulted in promoter demethylation together with re-expression of DAPK1 and both miRNAs. In primary APL samples, methylation of miR-34b/c was detected in 43% in contrast to absence of methylation of DAPK1, p14ARF or miR-34a. Overexpression of miR-34b in NB4 resulted in inhibition of proliferation.

Conclusions

Methylation of DAPK1, miR-34a and -34b/c is tumour-specific, and associated with gene/miRNAs silencing. miR-34b/c is a tumour suppressor miRNA in APL. Methylation of miR-34b/c may contribute to APL leukaemogenesis.

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