Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

Br J Cancer. 2006 Oct 23;95(8):1108-13. doi: 10.1038/sj.bjc.6603392.

Abstract

BRCA1 plays a pivotal role in the repair of DNA damage, especially following chemotherapy and ionising radiation. We were interested in the regulation of BRCA1 expression in acute myeloid leukaemia (AML), in particular in therapy-related forms (t-AML). Using real-time PCR and Western blot, we found that BRCA1 mRNA was expressed at barely detectable levels by normal peripheral blood granulocytes, monocytes and lymphocytes, whereas control BM-mononuclear cells and selected CD34+ progenitor cells displayed significantly higher BRCA1 expression (P=0.0003). Acute myeloid leukaemia samples showed heterogeneous BRCA1 mRNA levels, which were lower than those of normal bone marrows (P=0.0001). We found a high frequency of hypermethylation of the BRCA1 promoter region in AML (51/133 samples, 38%), in particular in patients with karyotypic aberrations (P=0.026), and in t-AML, as compared to de novo AML (76 vs 31%, P=0.0002). Examining eight primary tumour samples from hypermethylated t-AML patients, BRCA1 was hypermethylated in three of four breast cancer samples, whereas it was unmethylated in the other four tumours. BRCA1 hypermethylation correlated to reduced BRCA1 mRNA (P=0.0004), and to increased DNA methyltransferase DNMT3A (P=0.003) expression. Our data show that reduced BRCA1 expression owing to promoter hypermethylation is frequent in t-AML and that this could contribute to secondary leukaemogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Blotting, Western
  • Cell Line, Tumor
  • CpG Islands / genetics
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Down-Regulation / genetics
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • HL-60 Cells
  • Humans
  • Jurkat Cells
  • Leukemia, Myeloid / etiology
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Male
  • Middle Aged
  • Neoplasms / therapy
  • Promoter Regions, Genetic / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Radiotherapy / adverse effects

Substances

  • BRCA1 Protein
  • RNA, Messenger
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A