Epigenetic inactivation of DAPK1, p14ARF, mir-34a and -34b/c in acute promyelocytic leukaemia. Issue 7 (7th May 2014)

• Record Type: Journal Article
• Authors: Ng, Ho Yin; Wan, Thomas S; So, Chi Chiu; Chim, Chor Sang
• Is Part Of: Journal of clinical pathology. Volume 67:Issue 7(2014)
• Page Start: 626
• Page End: 631
• Publication Date: 2014-05-07
• Subjects: DNA -- CANCER GENETICS -- HAEMATO-ONCOLOGY; Pathology -- Periodicals; Pathology, Molecular -- Periodicals; 616.0705
• DOI: 10.1136/jclinpath-2014-202276
• Languages: English
• ISSNs: 0021-9746

Abstract

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 p14 ARF 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, p14 ARF, 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, p14 ARF, 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, p14 ARF 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.