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Epigenetic inactivation of DAPK1, p14ARF, mir-34a and -34b/c in acute promyelocytic leukaemia
  1. Ho Yin Ng1,
  2. Thomas S Wan2,
  3. Chi Chiu So2,
  4. Chor Sang Chim1
  1. 1Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong
  2. 2Department of Pathology, Queen Mary Hospital, University of Hong Kong, Hong Kong
  1. Correspondence to Professor Chor Sang Chim, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam Road, Hong Kong; jcschim{at}hku.hk

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.

  • DNA
  • CANCER GENETICS
  • HAEMATO-ONCOLOGY

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